UCSF DIABETES, ENDOCRINOLOGY & METABOLISM TRAINING PROGRAM FACULTY RESEARCH SUMMARIES

My current research includes both basic science and clinical investigation. My laboratory work is focused on two aspects of insulin-like growth factor (IGF) biology. First, we are exploring the mechanisms by which IGFs regulate the differentiation of skeletal muscle cells. In particular, we have focused on the unique ability of IGFs to stimulate both the proliferation and differentiation of these cells. Specifically, we have studied target genes of IGF action and intracellular signaling pathways which influence the decision of skeletal myoblasts to proliferate or differentiate in response to IGFs. We are currently assessing the roles of Erk 1 and 2 and Akt in mediating the switch in IGF-I action from inhibiting to stimulating the transcription of myogenin, a member of the MyoD family of transcription factors that is essential for myogenic differentiation. In addition, we are characterizing IGF-responsive regions in the myogenin gene, with specific focus on binding sites for Myocyte Enhancer Factor 2 and Serum Response Factor.

Since 2003, our lab has embarked on a second aspect of IGF biology: exploring the role of IGF signaling in the motility and invasiveness of human neuroblastoma (NBL) cells. In collaborative studies, we have observed that small molecule inhibitors of IGF-I receptor activation block NBL growth, survival, and motility.

With respect to clinical investigation, I am an active member of the UCSF Diabetes Center and am Co-Investigator for TrialNet, a multicenter NIH-sponsored study focused on developing therapies to prevent type 1 diabetes mellitus in high risk individuals.

In addition, we have recently identified and characterized novel activating mutations in the V2 vasopressin receptor that cause a syndrome of inappropriate antidiuretic hormone (SIADH)-like phenotype, yet without detectable ADH. We have named this syndrome “Nephrogenic Syndrome of Inappropriate Antidiuresis” (NSIAD) and have reported our findings in the New England Journal of Medicine (352:34-40, 2005). I am currently overseeing collaborative basic and clinical studies of NSIAD with the goals of further understanding the pathophysiology of this syndrome and potentially developing targeted treatments.

Selected References

Tiffin N, Adi S, Stokoe D, Wu NY, Rosenthal SM: Akt phosphorylation is not sufficient for IGF-stimulated myogenin expression, but must be accompanied by downregualtion of Erk ½ phosphorylation. Endocrinology 145(11):4991-4996, 2004.

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.

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 138(1): 128-31, 2006.

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