? SH2-B family members bind to the receptors for multiple growth factors and cytokines. SH2-B has been shown to be vital for NGF-mediated neuronal differentiation. In addition, SH2-B is highly expressed in 3T3-L1 and 3T3-F442A preadipocytes and enhances GH-induced changes in the actin cytoskeleton, membrane ruffling and cell motility in these cells. In mice, genetic deletion of the SH2-B gene results in obesity, metabolic syndrome, leptin resistance, and hyperphagia. These data suggest SH2-B may regulate adipogenesis. My preliminary data using 3T3-L1 and 3T3-F442A preadipocytes shows that cells with depressed levels of SH2-B due to siRNA exhibit enhanced differentiation into adipocytes. In contrast, 3T3-F442A cells stably overexpressing SH2-B( show depressed differentiation into adipocytes. These results suggest that SH2-B plays a negative role in adipocyte differentiation. I will test the hypothesis that SH2-B inhibits adipocyte differentiation at least in part by regulating genes and/or proteins that are involved in cell morphology.
Three aims are stated in this research proposal: 1) Determine whether stably overexpressing SH2-B( inhibits and siRNA of SH2-B enhances adipose differentiation of preadipocytes; 2) Determine genes regulated by SH2-B during adipogenesis using Affymetrix gene array and QT-PCR; 3) Identify SH2-B( binding partners that affect adipocyte differentiation. The project will help me achieve my long-term goal of pursuing an academic position in the research areas of Molecular Endocrinology and Cellular Physiology. It will utilize my past experience while exposing me to new techniques and new scientific areas including QT-PCR, Affymetrix gene array analysis, identification and analysis of new pathways, mechanisms of differentiation and obesity. Dr. Carter-Su's lab at the University of Michigan and her collaborators provide optimal environment for this project and my training. Adipose tissue excess or obesity, is an increasingly prevalent, serious health problem worldwide because it is associated with an increased risk of hypertension, type 2 diabetes, coronary heart disease, sleeping disorders, and cancers. By achieving these aims, we should gain insight into the mechanisms by which SH2-B regulates adipogenesis, thereby gaining more insight into how adipogenesis is regulated. This new information will better position us and others to discover new therapeutic interventions for obesity, the metabolic syndrome and diabetes. ? ?
| Berry, Daniel C; Jin, Hui; Majumdar, Avijit et al. (2011) Signaling by vitamin A and retinol-binding protein regulates gene expression to inhibit insulin responses. Proc Natl Acad Sci U S A 108:4340-5 |
| Jin, Hui; Lanning, Nathan J; Carter-Su, Christin (2008) JAK2, but not Src family kinases, is required for STAT, ERK, and Akt signaling in response to growth hormone in preadipocytes and hepatoma cells. Mol Endocrinol 22:1825-41 |
