Endocrinology and Metabolism

COMPLICATIONS OF DIABETES

Brief Description

This research program is designed to bring together clinician-scientists and basic scientists to investigate the cellular and molecular mechanisms by which hyperglycemia mediates its pathological effects. The program is divided into two major components: the first being investigation of the effects of high glucose on the b-cell; and the second, the pathogenesis of diabetic nephropathy and retinopathy. The program extends in scope from cell biology to in vivo physiology in rodents and humans, to the generation of animal models using transgenic and knockout technology.  Specific studies include microarray-based gene expression profiling of b-cell lines, cultured islets, mesangial cells, renal proximal tubular cells, and glomeruli from rodents with diabetes to identify the genes affected by high glucose. The signaling cascades activated by high glucose are assessed by proteomic analysis of kinase and phosphatase expression and substrate phosphorylation. The pathogenetic role of oxidative stress and the hexosamine biosynthesis pathway are also addressed.

Principal Investigators

Recent Original Research Publications

Goldberg HJ, Whiteside CI, Fantus IG. The hexosamine pathway regulates the plasminogen activator inhibitor-1 gene promoter and Sp1 transcriptional activation through protein kinase C-b₁ and -d. J Biol Chem 277:33833-33841, 2002.

Lam TKT, Yoshii H, Haber A, Bogdanovic E, Lam L, Fantus IG, Giacca A. Free fatty acid-induced hepatic insulin resistance:  a potential role for protein kinase C-d.  Am J Physiol  Endocrinol Metab 283:E682-E691, 2002.

Hua H, Goldberg HJ, Fantus IG, Whiteside CI. High glucose-enhanced mesangial cell extracellular signal-regulated protein kinase activation and a1 (IV) collagen expression in response to endothelin-1.  Role of specific protein kinase C isozymes.  Diabetes 50: 2376-2383, 2001.

Lewis GF, Carpentier A, Adeli A, Giacca A. Imbalance between fat storage in adipose and non-adipose tissue in the pathogenesis of insulin resistance and type 2 diabetes. Endo Rev, 23:201-229, 2002.

Wang X, Li H, De Leo D, Koshkin V, Fantus IG, Giacca A, Chan CB, Wheeler MB, Der S. Gene and protein kinase expression profiling of reactive oxygen species-associated lipotoxicity in the pancreatic b-cell line MIN6. (in preparation)

Future Directions

Future aims are to foster increased collaboration of the investigators focusing on common themes; provide integrated broad transdisciplinary training for students and postdoctoral fellows in a thematic approach; and bridge the cellular/molecular studies with in vivo integrative physiology in humans and with rodent models.

ENDOCRINE ONCOLOGY

Brief Description

An integrated, multidisciplinary program focussing on the clinical, educational, and fundamental basis of neoplasia of the endocrine system.

Principal Investigators

Recent Original Research Publications

George SR, O’Dowd BF, Lee SP. G protein-coupled receptor oligomerization: unexplored paths of drug discovery.  Nature Reviews Drug Discovery, 2002 (In press).

Boushey RP,  Yusta B, Drucker D J. Glucagon-like peptide (GLP)-2 reduces chemotherapy- associated mortality and enhances cell survival in cells expressing a transfected GLP-2 receptor. Cancer Res 61:687-693, 2001.

Ezzat S, Zheng L, Zhu XF, Wu GE, Asa SL. Targeted expression of a human pituitary tumor-derived isoform of fibroblast growth factor receptor 4 recapitulates pituitary tumorigenesis. J Clin Invest 109:69-78, 2002.

Yu S, Asa SL, Ezzat S. Fibroblast growth factor receptor 4 is a target for the zinc-finger tTranscription factor Ikaros in the pPituitary. Mol Endocrinol 16:1069-1078, 2002.

Asa SL, Ezzat S. The pathogenesis of pituitary tumors. Nature Reviews (Cancer) 2:836-849, 2002.

Future Directions

Develop an international-caliber program that will attract patients, trainees, and research support to a consolidated Endocrine-Oncology Site Group.