PEDIATRIC ENDOCRINOLOGY TRAINING PROGRAM
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO

Current research activities of our faculty are as follows:

·  Walter L. Miller, M.D .
·  Mark S. Anderson , M.D.
·  Daniel D. Bikle, M.D. Ph.D.
·  Jeffrey Bluestone, Ph.D.
·  James D. Bristow, M.D.
·  David Gardner, M.D.
·  Michael German , M.D.
·  Kathleen Giacomini, Ph.D.
·  Stephen E. Gitelman, M.D.
·  Ira D. Goldfine, M.D.
·  Melvin M. Grumbach, M.D.
·  Holly A. Ingraham, M.D.
·  Robert H. Lustig, M.D.
·  Synthia H. Mellon, M.D.
·  Anthony A. Portale, M.D.
·  Neil Risch, Ph.D.
·  Stephen M. Rosenthal, M.D.
·  Deepak Srivastava, M.D.
·  Christian Vaisse, M.D, Ph.D.
·  Keith R.Yamamoto, Ph.D.

Walter L. Miller, M.D.

Professor, Department of Pediatrics, the Metabolic Research Unit and the Center for Reproductive Sciences; Member, Biomedical Sciences Graduate Program and Program in Human Genetics; Chief, Division of Endocrinology and Director, Pediatric Endocrine Training Program.

Dr. Miller's laboratory studies the molecular biology of human steroid hormone biosynthesis and its disorders causing the congenital adrenal hyperplasias. Current efforts are focused primarily on five areas.
1) Structure and mechanism of action of the steroidogenic acute regulatory (StAR) protein. StAR facilitates the movement of cholesterol into mitochondria, which is the rate-limiting step in steroidogenesis. We have shown that mutations in the StAR gene cause congenital lipoid adrenal hyperplasia and that StAR acts on the outer mitochondrial membrane as a molten globule. Current efforts concern determining the mechanism by which it facilitates cholesterol transport.
2) Regulation of 17,20-lyase activity. A single enzyme, P450c17, catalyzes both the 17α hydroxylase activity needed for glucocorticoid synthesis and the 17,20-lyase activity needed for sex steroid synthesis. These two activities are regulated independently, both by phosphorylation of the enzyme and by tissue-specific availability of redox partners. We are studying the enzyme's structure, mutations that cause 17,20-lyase deficiency, the mechanism of its phosphorylation, and the enzyme's interaction with electron donors. These studies are aimed at elucidating the role of P450c17 in premature adrenarche and in the polycystic ovary syndrome.
3) The principal function of ACTH and the gonadotropins is to regulate transcription of genes for steroidogenic enzymes through the intermediacy of cAMP. We are studying the transcriptional regulation of the P450scc, P450c17, P450c21, P450 oxidoreductase and cytochrome b5 genes to identify, clone, and characterize the nuclear transcription factors specifically responsible for these activities.
4) The rate-limiting, hormonally regulated step in the bio-activation of vitamin D is 1α hydroxylation. In collaboration with Dr. Anthony Portale, we were the first to clone the cDNA and gene for this enzyme and characterized the first mutations causing 1α -hydroxylase deficiency (vitamin D-dependent rickets, type 1). We have characterized the mutations in 30 patients and are currently studying the transcriptional regulation of this gene.
5) P450 oxidoreductase (POR) is the protein that donates electrons to all microsomal P450 enzymes, and hence is required for their activity. Although POR knockout mice die in early development, we found that human POR mutations are viable, causing disordered steroidogenesis with and without Antley-Bixler syndrome. We have now delineated the genetic variation in POR, and are assessing the impact of POR sequence variants on the action of drug-metabolizing P450 enzymes.
Please also visit the Miller Lab's web site at www.ucsf.edu/wlmlab.

Honors (Selected)              

Ross Research Award from the Western Society for Pediatric Research
Edwin B. Astwood Award from the Endocrine Society
Albion O. Bernstein Award, New York State Medical Society
Clinical Endocrinology Trust Medal, British Endocrine Societies
Henning Anderson Prize (co-recipient with Drs. Bristow and Gitelman), European Society for Paediatric
       Endocrinology
Fellow, American Association for the Advancement of Science
Fellow, Molecular Medicine Society
Samuel Rosenthal Foundation Prize for Excellence in Academic Pediatrics
Clinical Investigator Award from The Endocrine Society

Recent Publications (Selected)

  1. Flück CE, Tajima T, Pandey AV, Arlt W, Okuhara K, Verge CF, Jabs EW, Mendonca BB, Fujieda K, Miller WL. Mutant P450 oxidoreductase causes disordered steroidogenesis with and without Antley-Bixler syndrome. Nature Genetics. 36:228-230, 2004.
  2. Pandey AV, Miller WL. Regulation of 17,20 lyase activity by cytochrome b5 and by phosphorylation of P450c17. J Biol Chem 280:13265-13271, 2005.
  3. Huang N, Pandey AV, Agrawal V, Reardon W, Lapunzina PD, Mowat D, Jabs EW, vanVliet G, Sack J, Flück CE, Miller WL. Diversity and function of mutations in P450 oxidoreductase in patients with Antley-Bixler syndrome and disordered steroidogenesis. Am J Hum Genet 76:729-749, 2005.
  4. Huang N, Dardis A, Miller WL. Regulation of cytochrome b5 expression by Sp3, GATA-6 and NF1-C in human adrenal NCI-4295A cells. Mol Endocrinol 19:2020-2034, 2005.
  5. Baker BY, Yaworsky DC, Miller WL. A pH-dependent molten globule transition is required for activity of the steroidogenic acute regulatory protein, StAR. J Biol Chem 280:41753-41760, 2005.
  6. Baker BY, Epand RF, Epand RM, Miller WL. Cholesterol binding does not predict activity of the steroidogenic acute regulatory protein, StAR. J Biol Chem 282: 10223-10232, 2007.
  7. Scott RR, Gomes LG, Huang N, VanVliet G, Miller WL. Apparent manifesting heterozygosity in P450 oxidoreductase deficiency and its effect on coexisting 21-hydroxylase deficiency. J Clin Endocrinol Metab 92: 2318-2322, 2007.
  8. Bose HS, Whittal RM, Ran Y, Bose M, Baker BY, Miller WL. StAR-like activity and molten globule behavior of StARD6, a male germ-line protein. Biochemistry 47:2277-2288, 2008.
  9. Tee MK, Dong Q, Miller WL. Pathways leading to phosphorylation of P450c17 and to the post-translational regulation of androgen biosynthesis. Endocrinology. 149: 6667-2677, 2008.
  10. Agrawal V, Huang N, Miller WL. Pharmacogenetics of P450 oxidoreductase: Effect of sequence variants on activities of CYP1A2 and CYP2C19. Pharmacogenet Genomic. 18:569-576, 2008.

Mark S. Anderson, M.D., Ph.D.

Associate Professor of Medicine, UCSF Diabetes Center; Member Biomedical Sciences Graduate Program

The main research interest of our laboratory group is to examine the genetic control of autoimmune disease to gain a better understanding of the mechanisms by which immune tolerance is broken. Recently, we generated a mouse model of a human autoimmune disease called APECED, which is classically manifested by an autoimmune attack directed at multiple endocrine organs. This disease is inherited in a monogenic autosomal recessive fashion and the causative gene was identified and is called Aire (for autoimmune regulator). Aire knockout mice, like their human counterparts, develop an autoimmune disease that is targeted to multiple organs. Interestingly, we can ascribe one of the primary defects in these mice to the thymus gland. Specifically, it appears that Aire helps protect against autoimmunity by helping direct the ectopic transcription of multiple self-antigens in thymic medullary epithelial cells. Studies in our laboratory are ongoing on this interesting model of autoimmune disease looking in greater detail how this defect results in the breaking of immune tolerance and what genes may interact with the Aire gene to protect against or worsen autoimmunity. In addition to these ongoing studies, our laboratory is also interested in developing other models of autoimmune disease by using transgenic, knockout, and knock-in approaches.

Honors (Selected)    

Pew Scholars Program in Biomedical Sciences
Member and contributor to Faculty of 1000, Autoimmunity Section
Howard Hughes Medical Institute Postdoctoral Award for Physician-Scientists
Chief Resident of Medicine, University of Minnesota

Recent Publications (Selected)

  1. Anderson MS, Bluestone JA. 2005. The NOD Mouse: A Model of Immune Dysregulation. Annu Rev Immunol 23: 447-485.
  2. M.S. Anderson, E. Venanzi, Z. Chen, S. Berzins, C. Benoist, and D. Mathis. "The cellular mechanism of aire control of T cell tolerance" Immunity 23:227-239, 2005.
  3. W. Jiang, M.S. Anderson, Bronson, R., Mathis, D., and Benoist, C. Modifier loci condition the autoimmunity induced by aire-deficiency. J Exp Med. 202:805-815, 2005.
  4. J. DeVoss, Y. Hou, K. Johannes, W. Lu, G.I. Liou, J. Rinn, H. Chang, R. Caspi, L. Fong, and M.S. Anderson, Spontaneous autoimmunity prevented by thymic expression of a single self-antigen. J. Exp. Med 203:2727-2735, 2006.
  5. J.J. DeVoss, and M.S. Anderson, Lessons on immune tolerance from the monogenic disease APS1. Current Opinion in Genetics & Development 2007 In Press.
  6. Zhang, L., Barker, J.M., Babu, S., Su, M., Stenerson, M., Cheng, M., Shum, A., Zamir, E., Badolato, R., Law, A., Eisenbarth, G.S., Anderson, M.S. A robust interferon immunoassay that is highly specific for patients with Autoimmune Polyglandular Syndrome Type 1, Clin Immun, 125: 131-137, 2007.
  7. Cheng, M., Shum, A., Anderson, M.S. What’s new in the Aire? Trends Immun. 28: 321-327, 2007.

Daniel D. Bikle M.D., Ph.D.

Professor of Medicine

Dr. Bikle's research concerns the hormonal regulation of calcium metabolism, and includes projects involving the classic target tissues of bone and intestine as well as non classic tissues including the skin. One project attempts to understand the molecular mechanisms by which 1,25(OH)2 D regulates intestinal calcium transport, in particular calcium transport across the brush border. Using an intestinal cell line, Caco2, we are overexpressing or blocking the expression of selected brush border proteins to determine whether such manipulations alter vitamin D regulated calcium transport in these cells. The second project is evaluating the effects of parathyroid hormone and insulin like growth factor-1 on bone formation, with particular interest in the effects of mechanical loading or unloading on the anabolic actions of these hormones, examining at the molecular level the signaling pathways mediating these hormones as affected by loading. The third project is examining the mechanisms by which calcium and 1,25(OH)2D regulate kertinocyte differentiation. We are focusing on the calcium receptor and the vitamin D receptor, and the signaling pathways and transcriptional events mediated by their activation.

Honors (Selected)

Fellow, American College of Physicians
American Society of Clinical Investigation
Western Association of Physicians
Association of American Physicians
Fellow, Molecular Medicine Society

Recent Publications (Selected)

  1. Bikle DD, Elalieh H, Chang S, Xie ZJ, Sundberg JP. Development and progression of alopecia in the vitamin D receptor null mouse. J Cell Phsiaol 207 : 340-353, 2006.
  2. Wang Y, Nishida S, Elalieh HZ, Long RK, Halloran BP, Bikle DD. The role of IGF-I signaling in regulating osteoclastogenesis. J Bone Min Res 21: 1350-1358, 2006.
  3. Wang Y, Nishida S, Sakata T, Elalieh HZ, Chang W, Halloran BP, Doty SB, Bikle DD. Insulin-like growth factor-I is essential for embryonic bone development. Endocrinology 147: 4753-4761, 2006.
  4. Hawker N, Pennypacker S, Chang S, Bikle D. Regulation of human epidermal keratinocyte differentiation by the vitamin D receptor and its coactivators DRIP205, SRC2, and SRC3. J Invest Dermatol 127: 874-880, 2007.
  5. Tu C-L, Chang W, Bikle DD. The role of the calcium sensing receptor in regulating intracellular calcium handling in human epidermal keratinocytes. J Invest Dermatol 127:1074-1083, 2007.
  6. Schauber J, Dorschner RA, Coda AB, Buchau AS, Liu PT, Kiken D, Helfrich YR, Kang, S, Elalieh HZ, Steinmeyer A, Zugel U, Bikle DD, Modlin RL, Gallo RL.  Injury enhances TLR2 function and antimicrobial peptide expression through a vitamin D dependent mechanism. J Clin Invest 117: 803-811, 2007.
  7. Xie Z, Bikle DD. The recruitment of phosphatidylinositol 3-kinase to the E-cadherin/catenin complex at the plasma membrane is required for calcium-induced phospholipace C-γ 1 activation and human keratinocyte differentiation. J Biol Chem 282:8695-8703, 2007.
  8. Dvorak MM, Chen T-H, Orwoll B, Garvey C, Chang W, Bikle DD, Shoback DM. Constitutive activity of the osteoblast Ca2+-sensing receptor promotes loss of cancellous bone.Endocrinology 148:3156-3163, 2007.
  9. Wang Y, Nishida S, Boudignon BM, Burghardt A, Elalieh HZ, Hamilton MM, Majumdar S, Halloran BP, Clemens TL, Bikle DD. The IGF-I receptor is required for the anabolic actions of parathyroid hormone on bone. J Bone Min Res 22:1329-1337, 2007.
  10. Schauber J, Oda U, Buchau AS, Steinmeyer A, Zugel U, Bikle DD, Gallo RL. Histone acetylation in keratinocytes enables control of the expression of cathelicidin and DC14 by 1,25 dihydroxyvitamin D3. J Invest Dermatol 128:816-824, 2008.

Bluestone, Jeffrey, Ph.D.

A.W. and Mary Margaret Clausen Distinguished Professor and Director, UCSF Diabetes Center

Dr. Bluestone’s research over the past 25 years concerns the fundamental events that regulate T cells during immune responses to autoantigens and transplantation antigens. The insights gained from these studies help in the development of a new generation of tolerogenic drugs that will “turn off” selected parts of the immune system, leaving the disease-fighting capabilities intact. Our efforts to modulate T cell activation have centered on understanding and altering the positive signals delivered by the antigen-specific T cell receptor and secondary, so-called co-stimulatory signals, or engaging the negative regulatory events such as CTLA-4 and PD-1 that control T cell signal transduction. The Cd28 studies have focused on defining a “genetic fingerprint” for the CD28 co-stimulatory pathway. The idea is that CD28 signaling leads to a unique set of up-regulated and down-regulated genes that leads to a differentiated T cell state. Additional studies focus on negative regulatory pathways to induce and control tolerance induction. Blockade of CTLA-4 interactions with the B7-1 but not B7-2 ligand and PD-1 ligation with PD-L1 but not PD-L2 ligand exacerbates immunity. We have shown that these pathways control both anergy induction and regulatory T cells function – altering the cell growth and survival, the differentiation state of the T cells and their ability to migrate into the inflammatory site. Another part of the lab is focused on regulatory T cells, so-called Tregs, and their involvement in autoimmunity and transplantation. We demonstrated that Foxp3+ Tregs from autoimmune diabetes-prone mice protect via a TGFβ-dependent pathway. These data provide an explanation for the tolerogenic effect of anti-CD3 antibodies and position them as the first example of a clinically applicable pharmacological stimulation of TGFβ producing regulatory CD4+ T cells. We are using cutting edge tools, such as two-photon microscopy and BAC transgenesis, to dissect the cellular interactions that control immunity in vivo.

Honors (Selected)

1989 – American Cancer Society Faculty Scholar
1997 – Guggenheim Senior Fellowship
1997 – Fogarty Senior Research Fellowship
1998 – Cornell Medical School Distinguished Alumni Award
2004 – Juvenile Diabetes Research Foundation Gerold & Kayla Grodsky Basic Science Award
2004 – American Society for Transplantation Roche Distinguished Research Award
2005 – Mary Tyler Moore & Robert Levine Excellence in Clinical Research Award,
    Juvenile Diabetes Research Foundation
2006 – Elected, American Academy of Arts and Sciences

Recent Publications (Selected)

  1. Bour-Jordan H, Thompson HL, Bluestone JA. Distinct effector mechanisms in the development of autoimmune neuropathy versus diabetes in nonobese diabetic mice. J Immunol 175:5649-5655, 2005.
  2. Herold KC, Gitelman SE, Masharani U, Hagopian W, Bisikirska B, Donaldson D, Rother K, Diamond B, Harlan DM, Bluestone JA. A single course of anti-CD3 monoclonal antibody hOKT3γ1 (Ala-Ala) results in improvement in c-peptide responses and clinical parameters for at least 2 years after onset of type 1 diabetes. Diabetes 54:1763-1769, 2005.
  3. Masteller EL, Warner MR, Tang Q, Tarbell KV, McDevitt H, Bluestone JA. Expansion of functional endogenous antigen-specific CD4+CD25+ regulatory T cells from NOD mice. J Immunol 175:3053-3059, 2005.
  4. Tang Q, Adams JY, Tooley AJ, Bi M, Fife BT, Serra P, Santamaria P, Locksley RM, Krummel MF, Bluestone JA. Visualizing regulatory T cell control of autoimmune responses in nonobese diabetic mice. Nat Immunol 7:83-92, 2006.
  5. Liu W, Putnam AL, Zhou X-Y, Szot GL, Lee MR, Zhu S, Gottlieb PK, Gingeras TR, de St. Groth BF, Clayberger C, Soper DM, Ziegler SF, Bluestone JA. CD127 expression inversely correlates with FoxP3 and suppressive function of human CD4+ T reg cells. J Exp Med 203:1701-1711, 2006.
  6. Fife BT, Griffin MD, Abbas AK, Locksley RM, Bluestone JA. Inhibition of T cell activation and autoimmune diabetes using a B cell surface-linked CTLA-4 agonist. J Clin Invest 116:2252-2261, 2006. Comment in: J Clin Invest 116:2080-2083, 2006.
  7. Fife BT, Guleria I, Gubbels-Bupp M, Eagar TN, Tang Q, Bour-Jordan H, Yagita H, Azuma M, Sayegh MH, Bluestone JA. Insulin-induced remission in new onset NOD mice is maintained by the PD-1-PD-L1 pathway. J Exp Med 203:2737-2747, 2006.
  8. Chikuma S, Bluestone JA. Expression of CTLA-4 and FOXP3 in cis protects from lethal lymphoproliferative disease. Eur J Immunol 37:1285-1289, 2007.
  9. You S, Leforban B, Gargia C, Bach JF, Bluestone JA, Chatenoud L. Adaptive TGF-beta-dependent regulatory T cells control autoimmune diabetes and are a privileged target of anti-CD3 antibody treatment. Proc Natl Acad Sci USA 104:6335-6340, 2007.
  10. Travis MA, Reizis B, Melton AC, Masteller E, Tang Q, Proctor JM, Wang Y, Bernstein X, Huang X, Reichardt L, Bluestone JA, Sheppard D. Loss of integrin αvβ8 on dendritic cells causes autoimmunity and colitis in mice. Nature 449:361-365, 2007.

James D. Bristow, M.D.

Professor of Pediatrics; Member, Biomedical Sciences Graduate Program.

Dr. Bristow's laboratory currently studies two main areas. The first concerns the biology of the extracellular matrix protein Tenascin-X, which is encoded by the TN-X gene, which overlaps the steroid 21-hydroxylase gene. Dr. Bristow has developed procedures to isolate and characterize this novel 450 kDa protein and has delineated its patterns of expression in the developing fetus, which suggest a role in connective tissue biology. To clarify the role of Tenascin-X in human biology, Drs. Bristow and Miller hypothesized that some TN-X gene deletions would cause a contiguous gene syndrome of severe 21-hydroxylase deficiency and a connective tissue disease. This approach now indicates that disruption of the TN-X gene causes an Ehlers-Danlos-like syndrome. The second area of interest is development of coronary arteries. Using quail-chick chimeras we have recently shown that epicardial cells undergo an epithelial-mesenchymal transformation and participate directly in coronary morphogenesis. The signals involved are now being studied using both in vitro and in vivo models.

Honors (Selected)

Henning Andersen Prize (co-recipient with Drs. Miller and Gitelman),
    European Society for Paediatric Endocrinology
Ross Research Award, Western Society for Pediatric Research

Recent Publications (Selected)

  1. Epting CL, Lopez JE, Shen X, Liu LS, Bristow J, Bernstein HS. Stem-cell antigen-1 is necessary for cell-cycle withdrawal and myoblast differentiation in C2C12 cells. J Cell Sci 117:6185-6195, 2004.
  2. Lindor NM, Bristow J. Tenascin-X deficiency in autosomal recessive Ehler-Danlos syndrome. Amer J Med Gen Part A 135A: 75-80, 2005.
  3. Rojas A, De Val S, Heidt AB, Xu SM, Bristow J, Black BL. Data4 expression in lateral mesoderm is downstream of BMP4 and is activated directly by Forkhead and GATA transcription factors though a distal enhancer element. Development 132: 3405-3417, 2005.
  4. Bristow J, Carey W, Egging D, Schalwijk J. Tenascin-X, collagen, elastin, and the Ehlers-Danlos syndrome. Amer J Med Gen Part C- Seminars in Medical Genetics 139C: 24-30, 20005.
  5. Weng L, Rubin EM, Bristow J. Application of sequence-based methods in human microbial ecology. Genome Research 16: 316-322, 2006.
  6. Tartaglia M, Pennacchio LA, Zhao C, Yadav KK, Fodale V, Sarkozy A, Pandit B, Oishi K, Martinelli S, Schackwitz W, Ustaszewska A, Martin J, Bristow J, Carta C, Lepri F, Neri C, Vasta I, Gibson K, Curry CJ, Siguero JP, Digilio MC, Zampino G, Dallapiccola B, Bar-Sagi D, Gelb BD. Gain-of-function SOS1 mutations cause a distinctive form of Noonan syndrome.Nat Genet 39:75-79, 2008
  7. Visel A, Bristow J, Pennacchio LA. Enhancer identification through comparative genomics. Semin Cell Dev Biol 18:140-52, 2007.
  8. Egging D, van den Berkmortel F, Taylor G, Bristow J, Schalkwijk J. Interactions of human tenascin-X domains with dermal extracellular matrix molecules. Arch Dermatol Res 298:389-396, 2007.
  9. Flanagan JL, Brodie EL, Weng L, Lynch SV, Garcia O, Brown R, Hugenholtz P, DeSantis TZ, Andersen GL, Wiener-Kronish JP, Bristow J. Loss of bacterial diversity during antibiotic treatment of intubated patients colonized with Pseudomonas aeruginosa. J Clin Microbiol 45:1954-1962, 2007.
  10. Marco EJ, Abidi FE, Bristow J, Dean WB, Cotter P, Jeremy RJ, Schwartz CE, Sherr EH. ARHGEF9 disruption in a female patient is associated with X linked mental retardation and sensory hyperarousal. J Med Genet 45:100-105, 2008.

David Gardner, MD

Professor in Residence, Diabetes Center

Our laboratory is interested in the hormonal regulation of cardiovascular and renal function. More specifically, we have focused our attention on the cardiac natriuretic peptides and their receptors, and the liganded vitamin D receptor system for investigation. While it is generally accepted that vitamin D plays an important role in the regulation of mineral (i.e. calcium and phosphorous) homeostasis and normal bone growth, there is a growing body of evidence suggesting that it also plays a palliative role in protecting the cardiovascular system from the effects of adverse stimuli. For example, it suppresses plasma renin levels and reduces blood pressure in the mouse and in humans, and it reverses cardiac hypertrophy seen in patients with end stage renal disease on dialysis. We have shown previously that vitamin D reverses various components of the hypertrophic phenotype in cultured cardiac myocytes, and that mice lacking the vitamin D receptor have significant cardiac hypertrophy, albeit in the presence of moderate hypertension. We are now completing the construction of a flox’d VRD allele with the intention of selectively deleting this gene in the myocardial cell. This will allow us to determine whether vitamin D truly suppresses myocyte hypertrophy independent of its effects extrinsic to the heart.

Honors (Selected)

2000 – Association of American Physicians
2001 – Fellow of the American Heart Association
2006 – Distinguished Scientist Award, Clinical Ligand Assay Society

Recent Publications (Selected)

  1. Kovacic-Milivojevic B, Roediger F, Almeida EAC, Damsky CH, Gardner DG, Ilic D. Focal adhesion kinase mediates both sarcomeric organization and transcriptional activation of genes associated with cardiac myocyte hypertrophy. Mol Biol Cell 12:2290-2307, 2001.
  2. Chen S, Cao L, Intengan HD, Humphreys M, Gardner DG. Osmoregulation of eNOS gene expression in inner medullary collecting duct cells. Role in activation of the type A natriuretic peptide receptor. J Biol Chem 277:32498-32504, 2002.
  3. Ilic D, Kovacic B, Jin F, Baumbusch C, Gardner DG, Damsky CH. FAK is required for blood vessel morphogenesis. Circ Res 92:300-307, 2003.
  4. Liang F, Webb P, Marimuthu A, Zhang S, Gardner DG. Triiodothyronine increases BNP gene transcription and amplifies endothelin-dependent BNP gene transcription and hypertrophy in neonatal rat ventricular myocytes. J Biol Chem 278:15073-15082, 2003.
  5. Anderson HDI, Rahmutula D, Gardner DG. Tumor necrosis factor-alpha inhibits endothelial nitric oxide synthase gene promoter activity in bovine aortic endothelial cells. J Biol Chem 279:963-969, 2004.
  6. Anderson HD, Wang F, Gardner DG. Role of the epidermal growth factor receptor in signaling strain-dependent activation of the brain natriuretic peptide gene. J Biol Chem 279:9287-9297, 2004.
  7. Chen S, Gardner DG. Suppression of the inhibitory kinases WEE1 and MYT1 correlates with endothelin-dependent proliferation of rat aortic smooth muscle cells. J Biol Chem 279:13755-13763, 2004.
  8. Chen S, Ni X-P, Humphrey M, Gardner DG. 1,25 dihydroxyvitamin D amplifies type A natriuretic peptide receptor expression and activity in target cells. J Am Soc Nephrol 16:329-339, 2005.
  9. Chen S, Qiong Y, Gardner DG. A role for p38 MAPK and the c-myc protooncogene in endothelin-dependent stimulation of rat aortic smooth muscle cell proliferation. Hypertension 47:252-258, 2006.
  10. Chen S, Olsen K, Grigsby C, Gardner DG. Liganded vitamin D receptor activates natriuretic peptide receptor gene transcription in inner medullary collecting duct cells. Kidney Int 72:300, 2007.

Michael German, MD

Professor of Medicine, Justine K. Schreyer Endowed Chair in Diabetes Research, Clinical Director of the UCSF Diabetes Center, Director Diabetes, Endocrinology and Metabolism (DEM) Training Program

The primary interest of my laboratory is the pancreatic beta-cell.  We focus on beta-cell development, regeneration and gene expression.  Translational interests include discovering where these processes break down in type 2 diabetes, and applying our knowledge to novel strategies for curing diabetes (type 1 and 2).  Several lines of investigation are being pursued by the laboratory:

Beta-Cell determination and differentiation: Using transgenic and gene knockout mice and in vitro differentiation assays, we are outlining the hierarchy of pancreatic transcription factors during beta-cell development, and identifying their individual roles.  Recently, we have begun to outline the role of microRNA in this hierarchy.
Beta-cell gene expression: Ongoing studies in the German lab examine the interactions of transcription factors involved in beta-cell differentiation and maintenance and the transcriptional response to glucose.
Beta-cell turnover: After birth, proliferation replaces neogenesis as the major source of new beta-cells and, together with the rate of apoptosis, determines beta-cell mass. Presently we are exploring the role of several G-protein coupled receptors and their ligands, and the role of neural signals.
Beta-cell replacement: Ultimately a cure for people with type 1 diabetes, as well as many people with type 2 diabetes, requires the replacement of the beta-cell.  The genes that control beta-cell development can drive the formation of beta-cells from undifferentiated progenitor cells or stem cells, while the signals that control proliferation can be used for beta-cell expansion.  We are generating methods using these genes to produce new beta-cells both in vitro and in vivo.

Type 2 Diabetes:  Type 2 diabetes results from increased insulin demand due to insulin resistance in a setting of limited insulin supply caused by beta-cell dysfunction.  In collaboration with other labs, we have been exploring the role of genes controlling beta-cell growth and replacement in determining the risk of type 2 diabetes.

Honors (Selected)

Kenneth R. Crispell Lecture, University of Virginia
Kroc Lecture, University of Alabama
Scholars Award from the Juvenile Diabetes Research Foundation
Member of the American Society for Clinical Investigation
Member of the Association of American Physicians

Recent Publications (Selected)

  1. Sander, M., Sussel, L., Conner, J., Schwitzgebel, V., Hayes-Jordan, A., German, M.  Homeobox gene Nkx6.1 lies downstream of Nkx2.2 in the major pathway of beta-cell formation in the pancreas Development 127: 5533-5540, 2000.
  2. Watada, H., Scheel, D., Leung, J., German, M. Distinct gene expression programs function in progenitor and mature islet cells. J Biol Chem 278(19):17130-17140, 2003.
  3. Wilson, M., Scheel, D., German, M. Gene expression cascades in pancreatic development.  Mechanisms of Development 120:65-80, 2003.
  4. Smith, S., Gasa, R., Watada, H., Wang, J., Griffen, S. and German, M. Neurogenin3 and Hepatic Nuclear Factor 1 cooperate in activating pancreatic expression of Pax4.  J. Biol. Chem 278:38254-38259, 2003.
  5. Mauvais-Jarvis, F., Smith, S., Le May, C.,  Leal,  S., Gautier, J., Molokhia, M., Riveline,  J., Rajan, A., Kevorkian, J., Zhang,  S., Vexiau, P., German, M., Vaisse, C., PAX4 gene variations predispose to ketosis-prone diabetes. Human Molecular Genetics 13:3151-3159, 2004.
  6. Gasa, R., Mrejen, C., Leachman, N., Otten, M., Barnes, M., Wang, J., Chakrabarti, S., Mirmira, R., German, M. Pro-endocrine genes coordinate the pancreatic islet differentiation program in vitro PNAS 101:13245–13250, 2004.
  7. Mauvais-Jarvis, F., Smith, S., Le May, C.,  Leal,  S., Gautier, J., Molokhia, M., Riveline,  J., Rajan, A., Kevorkian, J., Zhang,  S., Vexiau, P., German, M., Vaisse, C., PAX4 gene variations predispose to ketosis-prone diabetes. Human Molecular Genetics 13:3151-3159, 2004.
  8. Wilson, M.E. Yang, K.Y., Kalousova, A.,  Lau, J., Kosaka, Y.,  Lynn,  F.C., Wang, J., Mrejen, C., Episkopou, V., Clevers, H.C., and German, M.S. The HMG box transcription factor SOX4 is required for endocrine pancreas differentiation in mice.  Diabetes 54:3402-9, 2005.
  9. Lynn, F.C., Smith, S.B., Wilson, M.E., Yang, K.Y., Nekrep, N., German, M.S. Sox9 coordinates a transcriptional network in pancreatic progenitor cells. PNAS 104:10500-10505, 2007.
  10. Lynn, F.C., Skewes-Cox, P., Kosaka, Y., McManus, M.T., Harfe, B.D, and German, M.S. MicroRNA expression is required for pancreatic organogenesis. Diabetes 56:2938-2945, 2007.

Kathleen M. Giacomini, Ph.D.

Professor and Chair, Biopharmaceutical Sciences

Dr. Giacomini’s research is in the area of pharmacogenomics, genetic basis for variation in drug response. She is particularly interested in genetic variation in membrane transporters that play a role in drug targeting. She is leading a large research program to discover new variants in membrane transporters that play a critical role in drug response. Her work extends from cell and molecular biological studies to studies of clinical drug response in patient populations.

Honors (Selected)

Elected Fellow, American Association of Pharmaceutical Scientists
UCSF, Dr. Martin Luther King, Jr., Award for the Advancement of Women and Minorities
Vice President, American Society for Clinical Pharmacology and Therapeutics
1997 – UCSF, Chancellor’s Award for the Advancement of Women
1999 – Recognition Award for Distinguished Achievement of Filipino at UCSF
2001 – International Pharmaceutical Federation (FIP), Pharmaceutical Scientist of the Year
            Elected Fellow, American Association for the Advancement of Science
2005 – Paul Dawson Biotechnology Award, American Association of College of Pharmacy
2006 – Distinguished Scientist in Drug Metabolism, American Association of Pharmaceutical Scientists
2006 – Elected Member, Institute of Medicine
2007 – International Woman Scientist Award, Academy of Pharmaceutical Science & Technology, Japan
            Outstanding Researcher, International Pharmaceutical Sciences Federation

Recent Publications (Selected)

  1. Badagnani I, Castro R, Taylor TR, Brett CM, Huang CC, Stryke D, Kawamoto M, Ferrin SJ, Carlson EJ, Burchard EG, Giacomini KM. Interaction of methotrexate with organic-anion transporting polypeptide 1A2 and its genetic variants. J Pharmacol Exp Ther 318:521-529, 2006.
  2. Owen R, Badagnani I, Giacomini KM. Molecular determinants of specificity for synthetic nucleoside analogs in the concentrative nucleoside tarnsporter, CNT2. J Biol Chem 281:266875-266882, 2006.
  3. Roden DM, Altman RB, Benowitz NL, Flockhart DA, Giacomini KM, Johnson JA, Krauss RM, McLeod HL, Ratain MJ, Relling MV, Ring HZ, Shuldiner AR, Weinshilboum RM, Weiss ST. Pharmacogenomics: challenges and opportunities. Ann Intern Med Review 145:749-757, 2006.
  4. Urban TJ, Brown C, Castro RA, Shah N, Mercer R, Huang Y, Brett CM, Burchard EG, Giacomini KM. Effects of genetic variation in the novel organic cation transporter, OCTN1, on the renal clearance of gabapentin. Clin Pharmacol 83:416-421, 2008.
  5. Shu Y, Sheardown SA, Brown C, Owen RP, Zhang S, Castro RA, Ianculescu AG, Yue L, Lo JC, Burchard EG, Brett CM, Giacomini KM. Effect of genetic variation in the organic cation transporter 1 (OCT1) on metformin action. J Clin Invest  117:1422-1431, 2007.
  6. Shu Y, Brown C, Castro RA, Shi RJ, Lin ET, Owen RP, Sheardown SA, Yue L, Burchard EG, Brett CM, Giacomini KM. Effect of genetic variation in the organic cation transporter 1, OCT1, on metformin pharmacokinetics. Clin Pharmacol Ther 83:273-280, 2008 .
  7. Wilke RA, Lin DW, Roden DM, Watkins PB, Flockhart D, Zineh I, Giacomini KM, Krauss RM. Identifying genetic risk factors for serious adverse drug reactions: current progress and challenges. Nat Rev Drug Discov 6:904-916, 2007
  8. Huang N, Agrawal V, Giacomini KM, Miller WL. Genetics of P450 oxidoreductase: sequence variation in 842 individuals of four ethnicities and activities of 15 missense mutations. Proc Natl Acad Sci U S A 5;105:1733-1738, 2008 .
  9. Urban TJ, Brown C, Castro RA, Shah N, Mercer R, Huang Y, Brett CM, Burchard EG, Giacomini KM. Effects of genetic variation in the novel organic cation transporter, OCTN1, on the renal clearance of gabapentin. Clin Pharmacol Ther 83:416-421, 2008.
  10. Cropp CD, Komori T, Shima JE, Urban TJ, Yee SW, More SS, Giacomini KM. Organic anion transporter 2 (SLC22A7) is a facilitative transporter of cGMP. Mol Pharmacol 7:1151-1158, 2008.

Stephen E. Gitelman, M.D.

Professor of Clinical Pediatrics; Member, UCSF Diabetes Center; Director of Pediatric Diabetes Clinics, Mary B. Olney, M.D./KAK Chair in Pediatric Diabetes and Clinical Research

Dr. Gitelman's research interests primarily concern diabetes mellitus and disorders in water balance. Ongoing research studies include:
1)  Altering the natural course of type 1 diabetes mellitus by:
            a) optimizing means to screen and predict risk for development of type 1 diabetes,
            b) intervention trials to prevent the development of type 1 diabetes mellitus,
c) use of novel immunomodulatory agents at diagnosis to prolong endogenous insulin secretion (the honeymoon period)
These efforts are conducted through the NIH-sponsored TrialNet consortium, and the Immune Tolerance Network.
2)  Insulin pump therapy for children with diabetes.
3)  Improving metabolic control for Latino youth with type 1 diabetes.
4)  Obesity and type 2 diabetes in children.
5)  Characterization and treatment of water disorders in children.

Honors (Selected)

David W. Smith Pediatric Trainee Award, Western Society for Pediatric Research
Genentech Clinical Scholar Award, Lawson Wilkins Pediatric Endocrine Society
Henning Andersen Prize (co-recipient with Drs. Bristow and Miller) European Society for Paediatric
        Endocrinology

Recent Publications (Selected)

  1. Herold, KC, Hagopian, W, Auger, JA, Poumian-Ruiz, E, Taylor, L, Donaldson, D, Gitelman, SE, Harlan, DM, Xu, D, Zivin, RA, and Bluestone, JA. Anti-CD3 monoclonal antibody in new onset type 1 diabetes, New England J Med 346:1692-1698, 2002.
  2. Steele C, Hagopian WA, Gitelman SE, Masharani U, Cavaghan M, Rother K, Donaldson D, Harlan D, Bluestone J, Herold KC. Insulin secretion in type 1 diabetes. Diabetes 53:426-433, 2004.
  3. Wilson DM, Buckingham BA, Kunselman EL, Sullivan MM, Paguntalan HU, Gitelman SE. A two-center randomized controlled feasibility trial of insulin pump therapy in young children with diabetes. Diabetes Care 28:15-19, 2005.
  4. Feldman BJ, Rosenthal SM, Vargas GA, Fenwick RG, Huang EA, Matsuda-Abedani M, Lustig RH, Mathias RS, Portale AA, Miller WL, Gitelman SE. Nephrogenic syndrome of inappropriate antidivresis. Identification of novel activating mutations in the vasopressin type 2 receptor causing a newly described genetic disease. New England J Med 352: 1884-1890, 2005.
  5. Herold KC, Gitelman SE, Masharani U, Hagopian W, Bisikirska B, Donaldson D, Rother K, Diamond B, Harlan DM, Bluestone JA. A single course of anti-CD3 monoclonal antibody hOKT3 gamma 1(Ala-Ala) results in improvement in C-peptide responses and clinical parameters for at lease 2 7years after onset of type 1 diabetes. Diabetes 54:1763-1769, 2005.
  6. Sapru A, Gitelman SE, Bhatia S, Dubin RF, Newman TB, Flori H. Prevalence and characteristics of type 2 diabetes mellitus in 9-18 year-old children with diabetic ketoacidosis.  J Ped Endocrinol and Metabol 18: 865-872, 2004.
  7. Huang EA, Feldman BJ, Schwartz ID, Geller DH, Rosenthal SM, Gitelman SE. Oral urea for the treatment of chronic syndrome of inappropriate antidiuresis in children. J Peds 148:128-131, 2006.
  8. Seyfert-Margolis V, Gisler TD, Asare AL, Wang RS, Dosch HM, Brooks-Worrell B, Eisenbarth GS, Palmer JP, Greenbaum CJ, Gitelman SE, Nepom GT, Bluestone JA, Herold KC. Analysis of T-cell assays to measure autoimmune responses in subjects with type 1 diabetes: results of a blinded controlled study. Diabetes 55:2588-2594, 2006 .
  9. Rosenthal SM, Gitelman SE, Vargas GA, Feldman BJ. Gain-of-Function in the V2 Vasopressin Receptor. Horm Res 67:121-125, 2007.
  10. Bremer AA, Nobuhara KK, Gitelman SE. Congenital hyperinsulinism in an infant caused by a macroscopic insulin-producing lesion. J Pediatr Endocrinol Metab 20:437-440, 2007.

Ira D. Goldfine, M.D.

Professor of Medicine and Physiology

Our major research interests concern the regulation and transmembrane signaling mechanisms for insulin and other receptors. One major activity has been the molecular biology of the insulin receptor. We are currently investigating the nature of the insulin receptor gene and its regulation by glucocorticoids, insulin itself, differentiation and development. Studies are also being carried out to understand the regulation of the insulin receptor in a variety of hormonal and metabolic states. Concomitant studies in patients are being conducted to elucidate the cellular defects in insulin action that exist in adult onset diabetes.
One new area has been the elucidation of insulin receptor tyrosine kinase inhibitors. We have recently identified membrane glycoprotein PC-1 as an inhibitor of insulin receptor signaling in insulin resistant patients. A second area of investigation is the mechanism whereby the insulin receptor signals. The role of receptor kinase in signaling is being probed by receptor mutants and antireceptor antibodies. A third area is the role of insulin receptor overexpression in the biology of breast cancers.

Honors (Selected)

1963 – State of Illinois Scholar
1988 – Mary Jane Kugel Award, Juvenile Diabetes Foundation
1989 – Rosenthal Award, American College of Physicians
1993 – President, Insulin Receptor Society International
1995 – Mount Zion Distinguished Alumni Award
2002-03 – President, American Diabetes Association, Western Region
2003 – Williams-Levine Award, Western Metabolism Club
2006 – Italian Diabetes Association Mentor Award

Recent Publications (Selected)

  1. Dong HJ, Maddux BA, Altomonte J, Meseck M, Accili D, Terkeltaub R, Johnson K, Youngren JF, Goldfine ID. Increased hepatic levels of the insulin receptor inhibitor, PC-1/NPP1, induce insulin resistance and glucose intolerance. Diabetes 54:367-372, 2005.
  2. Youngren JF, Gable K, Penaranda C, Maddux BA, Zavodovskaya M, Lobo M, Campbell M, Kerner J, Goldfine ID. Nordihydroguaiaretic acid (NDGA) inhibits the IGF-1 and c-erbB2/HER2/neu receptors and suppress growth in breast cancer cells. Breast Cancer Research and Treatment 94: 31-46, 2005.
  3. Gable KL, Maddux BA, Pernaranda C, Zavodovskaya M, Campbell MJ, Lobo M, Robinson L, Schow S, Kerner JA, Goldfine ID, Youngren JF. Diarylureas are small-molecule inhibitors of insulin-like growth factor I receptor signaling and breast cancer cell growth. Mol Cancer Theraputics 5: 1079-1086, 2006.
  4. Maddux B, Chang Y-N, Accili D, McGuinness OP, Youngern FJ, Goldfine ID. Over-expression of the insulin receptor inhibitor PC-1/ENPP1 induces insulin resistance and hyper-glycemia. Am J Physiol Endocrinol Metab 290: E746-E749, 2006.
  5. Anderson MO, Yu H, Penaranda C, Maddux BA, Goldfine ID, Youngren JF, Guy RK. Parallel synthesis of diarylureas and their evaluation as inhibitors of insulin-like growth factor receptor. J Comb Chem 8:784-790, 2006 .
  6. Ryan CJ, Haqq CM, Simko J, Nonaka DF, Chan JM, Weinberg V, Small EJ, Goldfine ID. Expression of insulin-like growth factor-1 receptor in local and metastatic prostate cancer. Urol Oncolv 25:134-140, 2007.
  7. Albarracin CA, Fuqua BC, Evans JL, Goldfine ID. Chromium picolinate and biotin combination improves glucose metabolism in treated uncontrolled overweight to obese patients with type 2 diabetes. Diabetes Metab Res Rev 24:41-51, 2008.
  8. Ryan CJ, Harzstark AH, Rosenberg J, Lin A, Claros C, Goldfine ID, Kerner JF, Small EJ. A pilot dose-escalation study of the effects of nordihydroguareacetic acid on hormone and prostate specific antigen levels in patients with relapsed prostate cancer. BJU Int 101:436-9, 2008.
  9. Goldfine ID, Maddux BA, Youngren JF, Reaven G, Accili D, Trischitta V, Vigneri R, Frittitta L. The role of membrane glycoprotein plasma cell antigen 1/ectonucleotide pyrophosphatase phosphodiesterase 1 in the pathogenesis of insulin resistance and related abnormalities. Endocr Rev 29:62-75, 2008.
  10. Li X, Youngren JF, Hyun B, Sakkas GK, Mulligan K, Majumdar S, Masharani UB, Schambelan M, Goldfine ID. Technical evaluation of in vivo abdominal fat and IMCL quantification using MRI and MRSI at 3 T. Magn Reson Imaging. 26:188-197, 2008.

Melvin M. Grumbach, M.D.

Edward B. Shaw Professor of Pediatrics, Emeritus

Dr. Grumbach's interests center on 1) neuroendocrinology of puberty and of gonadotropin secretion, 2) disorders of sex determination and differentiation, and 3) hormonal and gene effects on growth and maturation. Current clinical studies center on the roles of aromatase and estrogen on bony maturation.

Honors (Selected)

Williams Leadership Award from the Endocrine Society
Koch Award (co-recipient with Dr. Selna Kaplan) from the Endocrine Society
Howland Award from the American Pediatric Society
Institute of Medicine of the National Academy of Sciences
American Academy of Arts and Sciences
National Academy of Sciences
Past President of The Lawson Wilkins Pediatric Endocrine Society, The Endocrine Society, and The American
    Pediatric Society

Recent Publications (Selected)

  1. Grumbach MM. Estrogen, bone, growth, and sex:  A sea change in conventional wisdom.  J. Pediatr Endocrinol Metab 13:1439-1455, 2000.
  2. Lo JC, Grumbach MM. Pregnancy outcomes in women with congenital virilizing adrenal hyperplasia. Endocrinol Metab Clinics NA 30:207-229, 2001.
  3. Grumbach MM. The neuroendocrinology of human puberty revisited. Hormone Res 57:2-14, 2002.
  4. Grumbach MM, Styne DM. Puberty: ontogeny, neuroendocrinology, physiology and disorders. In: Williams Textbook of Endocrinology, 9th ed., Wilson JD, Foster DW, Kronenberg HM, Larsen PR (eds). Philadelphia, PA: WB Saunders. pp 1509-1625, 1998.
  5. Grumbach MM, Biller BMK, Braunstein GD, Campbell KK, Carney JA, Godley PA, Harris EL, Lee JKT, Oertel YC, Posner MC, Schlechte JA, Wieand HS. Management of the clinically in apparent adrenal mass ("incidentaloma") Ann Int Med 138:424-429, 2003.
  6. Grumbach MM. Mutations in the symthesis and action of estrogen. Ann NY Acad Sci 1038:7-13, 2004
  7. Grumbach MM. A window of opportunity: The diagnosis of gonadotropin deficiency in the male infant. J Clin Endocrinol Metab 90:3122-3127, 2005.
  8. Lee JA, Grumbach MM, Clark OH. The optimal treatment for pediatric Graves' disease is surgery. J Clin Endocrinol Metab 92:801-803, 2007.

Holly A. Ingraham, Ph.D.

Professor of Physiology

Dr. Ingraham's laboratory studies how a subset of nuclear receptors contributes to embryonic and adult endocrine biology. We use molecular biology, mouse genetics and structural biology. In mice, targeted disruption of the orphan nuclear receptor, steroidogenic factor 1 (SF-1) leads to the loss of multiple endocrine tissues. Our work also shows that SF-1 gene dosage is crucial for organ development and organ “scaling”, that is to say, for maintaining and achieving proper organ size. As such, SF-1 heterozygous mice exhibit deficits in adrenal development resulting in an impaired response to stress. We are currently investigating why SF-1 gene dosage affects organ size. A new and growing focus for the lab is on hypothalamic development. Recent genetic discoveries of the leptin and orexin pathways, and their respective roles in satiety or sleep, have underscored the importance of the hypothalamus as a master controller of innate or non-cognitive behaviors. Our recent work shows that SF-1 controls terminal differentiation of the ventromedial hypothalamic (VMH) neurons. We are now developing genetic tools using mouse models to study the development and function of the VMH. Ultimately, we hope to understand the underlying molecular mechanisms of behaviors controlled by the VMH, including sexual and feeding behaviors.

Honors (Selected)

William Lectureship for Pediatric Research
Brook Byers Award
Sandler Opportunity Award

Recent Publications (Selected)

  1. Huber BR, Desclozeauz M, West BL, Cunha-Lima ST, Nyguen HI, Baxter JD, Ingraham HA, Fletterick RJ. Thyroid hormone receptor beta receptor mutations conferring hormone resistance and reduced corepressor release exhibit decreased stability in the N-terminal ligand-binding domain. Mol Endocrinol 17:107-116, 2003.
  2. Tran P, Marin O, Lee MK, Xu B, Reichardt LF, Jones KR, Rubenstein JR, Ingraham HA. Requirement of steroidogenic factor-1 in terminal differentiation of ventromedial hypothalamic neurons. Mol Cell Neurosci 22:441-453, 2003.
  3. Sablin E, Krylova I, Fletterick RJ, Ingraham HA. Structural basis for ligand-independent activation of the orphan nuclear receptor LRH-1. Molecular Cell 11:1575-1585, 2003.
  4. Jordan B, Shen J-H, Olaso RB, Ingraham HA, Vilain ER. Wnt4 overexpression disrupts normal testicular vasculature and inhibits testosterone synthesis by repressing SF-1/ a -catenin synergy. Proc Nat Acad Sci USA 100:10866-10871, 2003.
  5. Fowkes R, Alwin S, King P, Desclozeaux M, Ingraham HA, Burrin JM. SF-1 and the gonadotrope-specific element (GSE) enhance basal and PACAP-stimulated transcription of the human glycoprotein hormone a -subunit gene in gonadotropes. Mol Endrocrinol 17:2177-2188, 2003.
  6. Bland M, Fowkes RJ, Ingraham HA. Differential requirement for the SF-1 gene dosage in adrenal development versus adult endocrine function. Mol Endocrinol 18:941-952, 2004.
  7. Lee MK, Lebedeva L, Suzawa M, Desclozeaux M, Ingraham HA. Repression of orphan nuclear receptor activity via SUMO-modification and the Dead-Box Protein DP103 (Ddx20, Gemin-3) Mol Cell Biol 23:1879-1890, 2005.
  8. Krylova IN, Sablin EP, Moore J, Xu RX, Waitt GM, MacKay JA, Juzumiene D, Bynum JM, Madauss K, Montana V, Lebedeva L, Suzawa M, Williams JD, William SP, Guy RK, Thornton JW, Fletterick RJ, Willson TM, Ingraham HA. Structural analyses reveal phosphatidyl inositols as ligands for the NR5 orphan receptors SF-1 and LRH-1. Cell 120:343-355, 2005.
  9. Ingraham HA, Redinbo MR. Orphan nuclear receptors adopted by crystallography. Current Opinion in Structural Biol 15:708-715, 2005.
  10. Kurrasch DM, Cheung CC, Lee FY, Tran PV, Hata K, Ingraham HA. The neonatal ventromedial hypothalamus transcriptome reveals novel markers with spatially distinct patterning. J Neurosci. Dec 12;27:13624-13634, 2007 .

Robert H. Lustig, M.D.

Professor of Clinical Pediatrics, Director of Endocrine Outpatient Clinics

Dr. Lustig joined the UCSF Pediatric Endocrine faculty on Sept 1, 2001.  His research concerns the clinical investigation of the neuroendocrine origins and treatment of obesity. He is interested in how the negative feedback energy balance becomes dysfunctional, turning into a positive feedback (“vicious”) cyle.  His current studies concern: 1) the role of beta cell dysfunction and insulin hypersecretion in obesity; 2) the neural, hormonal, and genetic factors that predispose to leptin resistance; 3) the potential efficacy of somatostatin agonists as a treatment for hypothalamic obesity; 4) ethnic differences in the neuroendocrine control of fat mass; 5) the role of environmental obesogens in altering leptin sensitivity.

Recent Publications (Selected)

  1. Lustig RH, Sen S, Soberman JE, Velasquez-Mieyer PA. Obesity, leptin resistance, and the effects of insulin reduction. Intl J Obesity 28:1344-1348, 2004.
  2. Preeyasombat C, Bacchetti P, Lazaz AA, Lustig RH. Racial and etiopathologic dichotomies in insulin hypersecretion and resistance in obese children. J Pediatr 146:474-481, 2005.
  3. Rose SR, Danish RK, Kearney NS, Schreiber RE, Lustig RH, Burghen GA, Hudson MM. ACTH deficiency in childhood cancer survivors. Pediatric Blood and Cancer 45: 808-813, 2005.
  4. Isganaitis E, Lustig RH. Fast food, central nervous system insulin resistance, and obesity. Arteriosclerosis thrombosis and Vascular Biol 25: 2451-2462, 2005.
  5. Lustig RH. Pediatric endocrine disorders of energy balance. Reviews in Endocrine and Metobolic Disorders 6: 245-260, 2005.
  6. Lustig RH, Mietus-Snyder ML, Bacchetti P, Lazar AA, Velasquez-Meyer PA, Christensen ML. Insulin dynamics predict body mass index and z-score response to insulin suppression of sensitization pharmacotherapy in obese children. J Peds 148: 23-29, 2006.
  7. Lustig RH, Greenway F, Velasquez-Meyer PA, Heimburger D, Schumacher D, Smith D, Smith W, Soler N, Warsi N, Berg W, Maloney J, Benedetto J, Zhu W, Hohneker J. A multicernter, randomized, double-blind, placebo-controlled, dose-finding trial of a long-acting formulation of octreotide in promoting weight loss in obese adults with insulin hypersecretion. International Journal of Obesity 30: 331-341, 2006.
  8. Lustig RH. Childhood obesity: behavioral aberration or biochemical drive? Reinterpreting the First Law of Thermodynamics. Nature Clin Practice Endo Metab 2: 447-458, 2006.
  9. Mietus-Snyder ML, Lustig RH. Childhood obesity: adrift in the “limbic triangle.” Ann Rev Med 59: 119-134, 2008.
  10. Lustig RH, Weiss R. Disorders of energy balance. In: Sperling MA (ed), Pediatric Endocrinology , 3rd Edition. Elsevier, New York 788-838, 2008.

Synthia H. Mellon, Ph.D.

Professor, Dept of Obstetrics, Gynecology, and Reproductive Sciences, The Center for Reproductive Sciences, and the Metabolic Research Unit; Member, Biomedical Sciences Graduate Program.

Dr. Mellon's laboratory studies rodent models of the hormonal regulation of steroid hormone synthesis. Current efforts are focused on three areas:
1) Biosynthesis and action of steroid hormones in the brain. Our lab has shown that the rodent brain, especially in the fetus, contains the steroidogenic enzymes needed to produce two classes of steroids. One of these, alloprenanolone, appears to bind to GABAA receptors to promote endogenous anticonvulsant and anxiolytic activity. The other, dehydroepiandrosterone and its sulfate, respectively, regulate the outgrowth of neurites destined to become axons or dendrites, at least in part through NMDA receptors.
2) Use of neurosteroids in the treatment of neurologic disorders. We have recently identified a defect in allopregnanolone synthesis in the mouse model of Nieman-Pick Type C Disease. Treatment of affected mice with allopregnanolone in the neonatal period resulted in a marked delay in the onset of neurologic symptoms and a doubling of the life expectancy. We are presently exploring the mechanisms of these actions and the potential applicability of allopregnanolone treatment in the other mouse and human lysosomal storage diseases.
3) Transcriptional regulation of P450scc and P450c17 in the rodent adrenal, testis and brain. The mechanisms regulating P450scc and P450c17 transcription appear to be identical in the adrenal and testis, and recent effects have led to the cloning of novel candidate transcription factors. By contrast the P450scc promoter elements that are active in the brain appear to be wholly different.

Honors (Selected)

Richard B. Weitzman Award from the Endocrine Society

Recent Publications (Selected)

  1. Fujii E, Mellon SH: Regulation of uterine gamma-aminobutyric acid (A) receptor subunit expression throughout pregnancy.  Endocrinology 142:1770-1777, 2001.
  2. Griffin LD, Mellon SH: Biosynthesis of the neurosteroid 3 alpha hydroxy-4-pregnen-20-one (3a hp), a specific inhibitor of FSH release. Endocrinology . 142:4617-4622, 2001.
  3. Zhang PL, Compagnone NA, Fiore C, Vigne JL, Culp P, Musci TJ, Mellon SH. Developmental and gonadal expression of the transcription factor SET and its target gene, P450c17 (17 α hydroxylase/c17,20 lyase). DNA Cell Biol 20:613-624, 2001.
  4. Hammer F, Compagnone NA, Vigne JL, Bair S, Mellon SH: Transcriptional regulation of P450scc gene expression in the embryonic rodent nervous system. Endocrinology 145:901-912, 2004.
  5. Bair SR, Mellon SH: Deletion of the mouse P450c17 gene causes early embryonic lethality. Mol Cell Biol 24:5383-5390, 2004.
  6. Griffin LD, Gong W, Verot L, Mellon SH: Niemann-Pick type C disease involves disrupted neurosteroidogenesis and responds to allopregnanolone. Nature Medicine 704-711, 2004.
  7. Brake PB, Bair SR, Mellon SH. DNA sequence-dependent regulation of SF-1-mediated transcription. DNA and Cell Biol 24:148-160, 2005.
  8. Langmade SJ, Gale SE, Frolov A, Mohri I, Suzuki K, Mellon SH, Walkley SU, Covey DF, Schaffer JE, Ory DS. Pregnane X receptor (PXR) activation: a mechanism for neuroprotection in a mouse model of Niemann-Pick C disease. Proc Natl Acad Sci USA 12:13807-138128, 2006.
  9. Mellon SH, Bair SR, Depoix C, Vigne JL, Hecht NB, Brake PB. Translin coactivates steroidogenic factor-1-stimulated transcription. Mol Endocrinol 21:89-105, 2007.
  10. Mellon SH. Neurosteroid regulation of central nervous system development. Pharmacol Ther 116:107-124, 2007.

Anthony A. Portale, M.D.

Professor of Pediatrics and Medicine; Chief, Division of Nephrology

Dr. Portale's laboratory studies the regulation of the biosynthesis of 1,25(OH) 2 D, the hormonally active form of vitamin D.  Work concerns the regulation of 1,25(OH) 2 D by phosphorous and by PTH in healthy subjects and in patients with chronic renal disease, as well as in rodent model systems.  Together with Dr. Miller, Dr. Portale's laboratory cloned the human cDNA and gene for the 25-hydroxyvitamin D 1α -hydroxylase (P450c1α), which is the rate-limiting and hormonally regulated step in the bio-activation of vitamin D, and together the two laboratories have delineated the molecular genetics of mutations in the gene for  P450c1α that cause vitamin D-dependent rickets, type I (also known as pseudo-vitamin D deficient rickets, type I).  Current work concerns the roles of PTH, cAMP and phosphate in regulating the transcription of the P450c1α gene, both in human cell systems and in intact rats.

Recent Publications (Selected)

  1. Tenenhouse HS, Martel J, Ganthier C, Zhang MYH, Portale AA: Renal expression of the sodium/phosphate cotransporter gene,Npt2 , is not required for regulation of renal 1a -hydroxylase by phosphate. Endocrinology 142: 1124-1129, 2001.
  2. Zhang MYH, Wang XM, Wang JT, Compagnone NA, Mellon SH, Olson JL, Tenenhouse HS, Miller WL, Portale AA: Dietary phosphorus transcriptionally regulates 25-hydroxyvitamin in D-1α -hydroxylase gene expression in the proximal renal tubule. Endocrinology 143:587-595, 2002.
  3. Wang XM, Zhang MYH, Miller WL, Portale AA: Novel mutations in patients with 1α -hydroxylase deficiency that confer partial enzyme activity in vitro. J Clin Endocrinol Metab 87:2424-2430, 2002.
  4. Xie ZJ, Munson SJ, Huang N, Portale AA, Miller WL, Bikle DD. The mechanism of 1, 25-dihydrozyvitamin D3 auto-regulation in keratinocytes. J Biol Chem 277:36987-36990, 2002.
  5. Azam N, Zhang MYH, Wang XM, Tenenhouse HS, Portale AA. Disordered regulation and renal localization of 25-hydroxyvitamin D-1α -hydroxylase gene expression by phosphorus in X-linked hypophosphatemic (Hyp) mice. Endocrinology 144:3463-3468, 2003.
  6. Perward F, Azam N, Zhanf MYH, Yamashita T, Tenenhouse HS, Portale AA. Dietary and serum phosphorus regulate fibroblast growth factor 23 expression and 1,25-dihydroxyvitamin D metabolism in mice. Endocrinol 146:5358-5364, 2005.
  7. Matsuda-Abedeni M, Portale AA, Shah A, Neuhaus J, McEnhill M, Mathias RS. Persistent secondary hyperparathyroidism after renal transplantation in children. Pediatric Nephrology 21:413-418, 2006.
  8. Antoniucci DM, Yamashita T, Portale AA. Dietary phosphorus regulates serum fibroblast growth factor-23 concentrations in healthy men. J Clin Endocrinol Metab 91:3144-9, 2006.
  9. Kim CJ, Kaplan LE, Perwad F, Huang N, Sharma A, Choi Y, Miller WL, Portale AA. Vitamin D 1α-hydroxylase gene mutations in patients with 1α-hydroxylase deficiency. J Clin Endocrinol Metab 92:3177-3182, 2007.
  10. Perwad F, Zhang MY, Tenenhouse HS, Portale AA. Fibroblast growth factor 23 impairs phosphorus and vitamin D metabolism in vivo and suppresses 25-hydroxyvitamin D-1alpha-hydroxylase expression in vitro. Am J Physiol Renal Physiol 293:F1577-F1583, 2007.

Neil Risch, Ph.D.

Professor, Epidemiology and Biostatistics; Lamond Family Foundation Distinguished Professor in Human Genetics; Director, Institute for Human Genetics

Dr. Risch, a statistical geneticist and genetic epidemiologist, is involved in a variety of projects of both a theoretical and applied nature. These studies include both clinical and population genetic projects. For example, one study involves identification of genes underlying the torsion dystonias. To date, Dr. Risch and his collaborators have identified several genes for specific subtypes of idiopathic dystonia. Yet a number of variant forms remain unmapped. Current research involves additional mapping and positional cloning of these variant forms. Dr. Risch has also been involved in large, multi-site collaborative projects on genetic susceptibility to hypertension and cardiovascular disease endpoints (the NHLBI funded Family Blood Pressure Program, and the Reynolds Foundation funded Heart, Health and Heredity study). These projects involve linkage analysis, positional cloning, and population-based association studies. One of these studies recently led to the identification of regions on chromosomes 6 and 21 by admixture linkage disequilibrium analysis in African American subjects with hypertension. Over the next several years, he plans to expand the admixture studies to other cardiovascular and metabolic phenotypes in both African American and Hispanic study subjects. Dr. Risch also has a longstanding collaborative project underway, with Canadian colleagues, on genetic susceptibility to multiple sclerosis. These studies involve both genetic and environmental hypotheses. In the genetics realm, he plans to continue linkage and positional cloning projects on over 1,000 multi-case families, plus undertake new candidate gene studies as well as linkage disequilibrium approaches. A major focus will continue on examination of genetic contributions of the HLA region. He also plans to continue his population genetic studies, examining the relationship between genetic variation and social categories such as race and ethnicity, and the importance of these relationships for identifying genetic factors underlying common and complex diseases, as well as rarer, Mendelian forms. He also plans to continue his collaborative efforts with Drs. Kathleen Giacomini at UCSF and Catherine Schaefer at Kaiser Division of Research in Oakland on pharmacogenomics of membrane transporters, and specifically their role in response to antidepressant medications.

Honors (Selected)

1978 – UCLA University Fellowship
1982 – NIH Research Career Development Award
1987 – American Mental Health Fund Research Award
1996 – Raine Visiting Professorship, University of Western Australia
1996, 1998 – Invited Lecturer, Frontiers of Science Symposium, National Academy of Sciences
2001 – Invited Opening Plenary Speaker, International Congress of Human Genetics, Vienna, Austria
2001 – The Blaffer Honorary Lecture, M.D. Anderson Cancer Center, Houston, TX
2002 – Invited Lecturer in the Director’s Series, National Institutes of Health
2002 – Who’s Who in America
2003 – American Men and Women of Science
2004 – Curt Stern Award, American Society of Human Genetics

Recent Publications (Selected)

  1. Hallmayer J, Glasson EJ, Bower C, Petterson B, Croen L, Grether J, Risch N. On the twin risk in autism. Am J Hum Genet 71:941-946, 2002.
  2. Botstein D, Risch N. Discovering genotypes underlying human phenotypes: past successes for mendelian disease, future approaches for complex disease. Nat Genet 33 Suppl:228-237, 2003.
  3. Risch N, Tang H, Katzenstein H, Ekstein J. Geographic distribution of disease mutations in the Ashkenazi Jewish population supports genetic drift over selection. Am J Hum Genet 72:812-822, 2003.
  4. Burchard EG, Ziv E, Coyle N, Lin-Gomez S, Tang H, Karter AJ, Mountain JL, Perez-Stable EJ, Sheppard D, Risch N. The importance of race and ethnic background in biomedical research and clinical practice. N Engl J Med 348:1170-1175, 2003.
  5. Mountain JL, Risch N. Assessing genetic contributions to phenotypic differences among “racial” and “ethnic” groups. Nat Genet 36(11 suppl.):S48-53, 2004.
  6. Jorgenson E, Tang H, Gadde M, Province M, Leppert M, Kardia S, Schork N, Cooper R, Rao DC, Boerwinkle E, Risch N. Ethnicity and human genetic linkage maps. Am J Hum Genet 76:276-290, 2005. (Winner of the Cotterman Prize, American Society of Human Genetics, 2005.)
  7. Gonzales Burchard E, Borrell LN, Choudhry S, Naqvi M, Tsai HJ, Rodriguez-Santana JR, Chapela R, Rogers SD, Mei R, Rodriguez-Cintron W, Arena JF, Kittles R, Perez-Stable EJ, Ziv E, Risch N. Latino populations: a unique opportunity for the study of race, genetics and social environment in epidemiological research. Am J Pub Health 95:2161-2168, 2005.
  8. Tang H, Jorgenson E, Gadde M, Karda SL, Rao DC, Zhu X, Schork NJ, Hanis CL, Risch N. Racial admixture and its impact on BMI and blood pressure in African and Mexican Americans. Hum Genet 119:624-633, 2006.
  9. Tang H, Coran M, Wang P, Zhu X, Risch N. Reconstructing genetic ancestry blocks in admixed individuals. Am J Hum Genet 79:1-12, 2006.
  10. Risch NJ, Bressman SB, Senthil G, Ozelius LJ. Intragenic Cis and Trans modification of genetic susceptibility in DYT1 torsion dystonia. Am J Hum Genet 80:1188-1193, 2007.

Stephen M. Rosenthal, M.D.

Professor of Pediatrics; Associate Program Director, Director, Pediatric Endocrine Outpatient Clinic, Member, UCSF Diabetes Center

Dr. Rosenthal’s research concerns two aspects of hormone receptor signaling. First, we have now extended our work in Insulin-like growth factor (IGF)-I receptor signaling to studies in human neuroblastoma (NBL). We are exploring the role of IGF signaling in the growth, motility, and invasiveness of human NBL cells. In collaborative studies, we have observed that small molecule inhibitors of the IGF-I receptor block growth, survival, and motility of NBL cells, and inhibit NBL growth in vivo in a xenograft model in nude mice. Second, Dr. Rosenthal and colleagues have recently identified and characterized novel activating mutations in the vasopressin V2 receptor (V2R) that cause a Syndrome of Inappropriate Antidiuretic Hormone (SIADH)-like phenotype, yet without detectable ADH. Dr. Rosenthal is currently engaged in collaborative studies to extend their characterization of NSIAD, with three specific aims: 1) explore further the molecular mechanisms responsible for the constitutive activity of the vasopressin V2R mutants, 2) further characterize the clinical phenotype of NSIAD patients and heterozygous carriers, and 3) explore the potential role of selective vasopressin V2R “inverse agonists” as a targeted treatment for this condition. Dr. Rosenthal is also an investigator in studies of Type 1 Diabetes and in studies related to growth disorders. Dr. Rosenthal is an active member of the UCSF Diabetes Center and is co-Investigator for TrialNet, a multi-center NIH-sponsored study focused on developing therapies to prevent Type 1 Diabetes Mellitus in high risk individuals. He is co-Investigator on the TrialNet Natural History of Type 1 Diabetes study and on three intervention studies for patients with newly diagnosed Type 1 Diabetes : 1) TrialNet Mycophenolate Mofetil-Dacluzimab (MMF-DZB), 2) TrialNet Rituximab, and 3) Immune Tolerance Network Phase II trial of hOKT3 gamma1 (Ala-Ala). Dr. Rosenthal is also the UCSF-site Principal Investigator for a multi-center trial investigating the therapeutic potential of recombinant human IGF-I for prepubertal children with Growth Hormone resistance.

Recent Publications (Selected)

  1. Tiffin N, Adi S, Stokoe D, Wu N-Y, Rosenthal SM: Akt phosphorylation is not sufficient for IGF-stimulated myogenin expression, but must be accompanied by downregulation of Erk ½ phosphorylation. Endocrinology 145:4991-4996, 2004.
  2. Feldman BJ*, Rosenthal SM*, Vargas GA, Fenwick RG, Huang EA, Matsuda-Abedini M, Lustig RH, Mathias RS, Portale AA, Miller WL, Gitelman SE. Nephrogenic syndrome of inappropriate antidiuresis. N Engl J Med 352: 34-40, 2005. *denotes co-first author
  3. Dong Q, Rosenthal SM. Endocrine disorders of the hypothalamus and pituitary. In: Pediatric Neurology, 4th edition. Swaiman KF, Ashwal S, Ferriero DM (eds). Mosby, Inc. (Elsevier, Inc.), Philadelphia, PA, 2006, pp. 2113-2127.
  4. Rosenthal SM, Feldman BJ, Vargas GA, Gitelman SE. Nephrogenic syndrome of inappropriate antidiuresis (NSIAD): A paradigm for activating mutations causing endocrine disease. Pediatr Endocrinol Rev, Volume 4, Suppl 1:66-70, 2006.
  5. Huang EA, Feldman BJ, Schwartz ID, Geller DH, Rosenthal SM, Gitelman SE. Oral urea for the treatment of chronic syndrome of inappropriate antidiuresis in children. J Pediatr 148:128-131, 2006.
  6. Bremer AA, Feldman BJ, Iezza G, Clark OH, Rosenthal SM. Report of a hürthle cell neoplasm in a peripubertal girl. Thyroid 17:175-178, 2007.
  7. Rosenthal SM, Gitelman SE, Vargas GA, Feldman BJ. Gain-of-Function in the V2 Vasopressin Receptor. Horm Res 2007;67 (suppl. 1):121-125
  8. Meyer GE, Chesler L, Liu D, Youngren J, Goldfine ID, Weiss MA, Matthay KK, Rosenthal SM. M nordihydroguaiaretic acid inhibits insulin-like growth factor signaling, growth and survival in human neuroblastoma cells. J Cell Biochem 102:1529-1541, 2007.
  9. Rosenthal S, Cohen P, Clayton P, Backeljauw P, Bang P, Ten S. Treatment perspectives in Idiopathic Short Stature with a focus on IGF-I deficiency (Guest Editor: Rosenfeld RG). Pediatr Endocrinol Rev, Volume 4, Suppl 2:251-271, 2007.

Deepak Srivastava, M.D.

Director, Gladstone Institute of Cardiovascular Disease; Professor, Departments of Pediatrics and Biochemistry & Biophysics; Wilma and Adeline Pirag Distinguished Professor in Pediatric Developmental Cardiology

Our laboratory focuses on the fundamental events involved in cell fate determination and differentiation and organogenesis. Specifically, we investigate the molecular events regulating developmental decisions that instruct cardiac progenitor cells to adopt a cardiac cell fate and subsequently fashion a functioning heart. We focus on transcriptional and post-transcriptional steps, particularly those involving microRNAs. We also investigate the causes of human cardiovascular disease by applying modern genetic technologies for the study of complex traits such as congenital heart disease. By using fly, mouse, and human genetics, we hope to develop a broad understanding of the biology underlying cardiogenesis and cardiovascular disorders.

Honors (selected)

1995   AHA–Young Investigator Award, Society for Pediatric Research Fellows–Research Award, March of Dimes–Basil O’Connor Award
1996   AHA–Louis B. Katz Young Investigator Award Finalist
1997   University of Michigan–Patrick J. Niland Memorial Lecturer
1998   Society for Pediatric Research–Richard Rowe Award in Pediatric Cardiology, Perinatal Research Society–Young Investigator Award
2000   Denison Young Memorial Lecturer, UTSW–Joel B. Steinberg Chair in Pediatrics; UTSW–Pogue Distinguished Chair in Research on Cardiac Birth            Defects
2005   Wilma and Adeline Pirag Distinguished Professorship in Pediatric Developmental Cardiology, UCSF
2006   Goldberg Lecturer, Cedars Sinai
2007   E. Mead Johnson Award, Society for Pediatric Research

Selected Publications

  1. Garg V, Kathiriya IS, Barnes R, Schluterman MK, King IN, Butler CA, Rothrock CR, Eapen RS, Hirayama-Yamada K, Joo K, Matsuoka R, Cohen JC, Srivastava D. (2003) GATA4 mutations cause human congenital heart defects and reveal an interaction with TBX5. Nature 424:443–447.
  2. Bock-Marquette I, Saxena A, White MD, Dimaio JM, Srivastava D. (2004) Thymosin beta4 activates integrin-linked kinase and promotes cardiac cell migration, survival and cardiac repair. Nature 432:466–472.
  3. Zhao Y, Samal E, Srivastava D. (2005) Serum response factor regulates a muscle-specific mircroRNA that targets Hand2 during cardiogenesis. Nature 436:214-220.
  4. Garg V, Muth AN, Ransom JF, Schluterman MK, Barnes R, King IN, Grossfeld PD, Srivastava D. (2005) Mutations in NOTCH1 cause aortic valve disease. Nature 437:270–274.
  5. Kwon C, Han Z, Olson EN, Srivastava D. (2005) MicroRNA1 influences cardiac differentiation in Drosophila and regulates Notch signaling. Proc Natl Acad Sci USA 102:18986–18991.
  6. Srivastava D, Ivey KN. (2006) Potential of stem cell-based therapies for heart disease. Nature 441:1097–1099.
  7. Srivastava D. (2006) Making or breaking the heart: From lineage determination to morphogenesis. Cell126:1037–1048.
  8. Zhao Y, Ransom JF, Li A, Vedantham V, von Drehle M, Muth AN, Tsuchihashi T, McManus MT, Schwartz RJ, Srivastava D. (2007) Dysregulation of cardiogenesis, cardiac conduction, and cell cycle in mice lacking miRNA-1-2. Cell 129:303–317.
  9. Kwon C, Arnold J, Hsiao EC, Taketo MM, Conklin BR, Srivastava D. (2007) Canonical Wnt signaling is a positive regulator of mammalian cardiac progenitors. Proc Natl Acad Sci USA 104:10894–10899.
  10. Jia H, King IN, Chopra SS, Wan H, Ni TT, Jiang C, Guan X, Wells S, Srivastava D, Zhong TP. Vertebrate heart groth is regulated by functional antagonism between Gridlock and Gata5. PNAS. 35: 14008-14013, 2007.

Christian Vaisse, M.D., Ph.D.

Professor of Medicine

The overall goal of this laboratory is to identify genetic defects implicated in the onset and progression of multi-factorial metabolic diseases such as obesity and diabetes. Our strategy combines human genetic approaches with molecular biology and animal studies. We are currently concentrating our research on the molecular mechanisms implicated in the hypothalamic effects of the adipocyte secreted, weight regulating hormone, leptin. After describing the first leptin receptor mutation in severely obese humans, we recently found that genetic alterations in the Melanocortin 4 receptor (MC4R), a mediator of the hypothalamic effects of leptin, are responsible for a more common form of human obesity. Using large scale automated screening procedures we now further investigate the frequency of mutations in the MC4R gene in large cohorts of obese patients. In parallel we also search for obesity causing mutations in additional candidate genes downstream the leptin pathway. Finally, both through in vitro and in vivo studies we are aiming to understand how these mutations cause obesity and what the implications are for the treatment of this condition.

Selected Publications

  1. Lubrano-Berthelier C, Le Stunff C, Bougnères P, Vaisse C. A homozygous null mutation delineates the role of the melanocortin-4 receptor in humans. J Clin Endocrinol Metab 89:2028-2032, 2004.
  2. Srinivasan S, Lubrano-Berthelier C, Govaerts C, Picard F, Santiago P, Conklin BR, Vaisse C. Constitutive activity of the melanocortin-4 receptor is maintained by its N-terminal domain and plays a role in energy homeostasis in humans.J Clin Invest 114:1158-1164, 2004.
  3. Picard F, Robin S, Lavielle M, Vaisse C, Daudin JJ. A statistical approach for array CGH data analysis. BMC Bioinformatics 6:27, 2005.
  4. Elefteriou F, Ahn JD, Takeda S, Starbuck M, Yang X, Liu X, Kondo H, Richards WG, Bannon TW, Noda M, Clement K, Vaisse C, Karsenty G. Leptin regulation of bone resorption by the sympathetic nervous system and CART. Nature 434:514-520, 2005.
  5. Sobngwi E, Gautier JF, Kevorkian JP, Villette JM, Riveline JP, Zhang S, Vexiau P, Leal SM, Vaisse C, Mauvais-Jarvis F. High prevalence of glucose-6-phosphate dehydrogenase deficiency without gene mutation suggests a novel genetic mechanism predisposing to ketosis-prone diabetes. J Clin Endocrinol Metab 90:4446-4451, 2005.
  6. Swarbrick MM, Waldenmaier B, Pennacchio LA, Lind DL, Cavazos MM, Geller F, Merriman R, Ustaszewska A, Malloy M, Scherag A, Hsueh WC, Rief W, Mauvais-Jarvis F, Pullinger CR, Kane JP, Dent R, McPherson R, Kwok PY, Hinney A, Hebebrand J, Vaisse C. Lack of support for the association between GAD2 polymorphisms and severe human obesity. PLoS Biol 3:e315, 2005.
  7. Govaerts C, Srinivasan S, Shapiro A, Zhang S, Picard F, Clement K, Lubrano-Berthelier C, Vaisse C. Obesity-associated mutations in the melanocortin 4 receptor provide novel insights into its function. Peptides 26:1909-1919, 2005.
  8. Lubrano-Berthelier C, Dubern B, Lacorte JM, Picard F, Shapiro A, Zhang S, Bertrais S, Hercberg S, Basdevant A, Clement K, Vaisse C. Melanocortin 4 receptor mutations in a large cohort of severely obese adults: prevalence, functional classification, genotype-phenotype relationship, and lack of association with binge eating. J Clin Endocrinol Metab 91:1811-1818, 2006.
  9. Ahituv N, Kavaslar N, Schackwitz W, Ustaszewska A, Martin J, Hebert S, Doelle H, Ersoy B, Kryukov G, Schmidt S, Yosef N, Ruppin E, Sharan R, Vaisse C, Sunyaev S, Dent R, Cohen J, McPherson R, Pennacchio LA. Medical sequencing at the extremes of human body mass. Am J Hum Genet 80:779-791, 2007.
  10. Dubern B, Lubrano-Berthelier C, Mencarelli M, Ersoy B, Frelut ML, Bouglé D, Costes B, Simon C, Tounian P, Vaisse C, Clement K. Mutational analysis of the pro-opiomelanocortin gene in French obese children led to the identification of a novel deleterious heterozygous mutation located in the alpha-melanocyte stimulating hormone domain. Pediatr Res 63:211-216, 2008.

Keith R. Yamamoto, Ph.D.

Professor of Cellular and Molecular Pharmacology; Executive Vice Dean, School of Medicine

Dr. Yamamoto's laboratory studies the activity of the intracellular receptors (IRs), including receptors for glucocorticoids (GR) and androgens (AR) in signal transduction, transcriptional regulation and physiological control. These hormone-receptor complexes bind to specific DNA sequences termed hormone response elements, which enhance or repress linked promoters. Our goal is to understand the molecular and cellular logic by which IRs integrate multiple signaling inputs to produce specific, distinct cellular and physiologic effects.
We have defined receptor domains for hormone and DNA binding, dimerization, nuclear localization, phosphorylation, interaction with various cellular factors and transcriptional regulation. IRs are functional in simpler organisms such as yeast, Drosophila and C. elegans, thus facilitating genetic analyses of their action and identification of other factors involved in its activities. We are pursuing 3D structure analyses of various domains of the receptor, and we employ biochemical strategies with purified components for mechanistic analyses. In mouse models and human cells, we mimic physiologic and pathologic states, for analyses of ligand chemistry for mechanistic and potential therapies. Thus, we use IRs as “biological probes” to define how a single regulatory protein can specify diverse patterns of specific gene expression and physiologic outcomes in different contexts.

Honors (Selected)

UCSF Distinguished Teaching Award
Dreyfus Teacher-Scholar Award
Elected Member, American Academy of Arts and Sciences
Elected Member, National Academy of Sciences
Gregory Pincus Medal
Elected Member, American Academy of Microbiology
Faculty Researcher Lecturer, UC San Francisco
Iowa State University Distinguished Achievement Citation
Vanderbilt Medal of Merit, Vanderbilt University
Iowa State University D.Sc., honorary
Elected Fellow, American Association for the Advancement of Science
Elected Fellow, Institute of Medicine

Recent Publications (Selected)

  1. Rogatsky I, Wang J-C, Derynck MK, Nonaka D, Khodabakhsh DB, Haqq CM, Darimont BD, Garabedian MJ, Yamamoto KR. Target-specific utilization of transcriptional regulatory surfaces by the glucocorticoid receptor. Proc Natl Acad Sci USA 100:13845-13850, 2003.
  2. Van Gilst MR, Hadjivassiliou H, Jolly A, Yamamoto KR. Nuclear hormone receptor NHR-49 controls fat consumption and fatty acid composition in C. elegans. PLoS Biol 3, 353, 2005
  3. Luecke HF, Yamamoto KR. The Glucocorticoid Receptor blocks P-TEFb recruitment by NF kB to effect promoter specific transcriptional repression. Genes Dev. 19: 1116-1127, 2005.
  4. Van Gilst MR, Hadjivassiliou H, Yamamoto KR. A Caenorhabditis elegans nutrient response system partially dependent on nuclrear receptor NHR-49. Proc Natl Acad Sci 102: 13496-13501, 2005.
  5. Wang JC, Shah N, Pantoja C, Meijsing SH, Ho JD, Scanlan TS, Yamamoto KR. Novel arylpyrazole compounds selectively modulate glucocorticoid receptor regulatory activity. Genes and Development 20 : 689-699, 2006.
  6. Feldman BF, Streeper RS, Farese RV, Jr, Yamamoto KR. Myostatin modulates adipogenesis to generate adipocytes with favorable metabolic effects. Proc Natl Acad Sci USA 103:15675-15680, 2006.
  7. Ricketson D, Hostick U, Fang L, Yamamoto KR, Darimont B. A conformational switch in the ligand binding domain regulates the dependence of the glucocorticoid receptor on Hsp90. J Mol Biol 368:729-741, 2007.
  8. So AY, Chaivorapol C, Haqq CM, Li H, Yamamoto KR. Cell- and gene-specific transcriptional regulation by the glucocorticoid receptor. PloS Genetics 3:e94, 2007.
  9. Bolton EC, So AY, Chaivorapol C, Haqq CM, Li H, Yamamoto KR. Cell- and gene-specific regulation of primary target genes by the androgen receptor. Genes Dev 21:2005-2017, 2007.
  10. Woodruff PG, Boushey HA, Dolganov GM, Barker CS, Yang YH, Donnelly S, Ellwanger A, Sidhu SS, Dao-Pick TP, Pantoja C, Erle DJ, Yamamoto KR, Fahy JV. Genome-wide profiling identifies epithelial cell genes associated with asthma and with treatment response to corticosteroids. Proc Natl Acad Sci USA 104:15858-15863, 2007.

Back to home

Updated August 4, 2009