Cell Cycle Regulators in Pancreatic Development and Disease
Several years ago we generated mouse models that led to the revelation of the role of the cell cycle machinery, specifically of Cdk4, in regulation of beta-cell mass. These mouse models revealed a crucial role for Cdk4, and the cell cycle machinery, in regulation of beta-cell mass with potential clinical applications for diabetes therapy. These studies imply that the beta-cell is uniquely sensitive to alterations in the cell cycle machinery. However, there remain a plethora of unresolved issues. (A) Although the beta-cell is capable of proliferation in response to physiological demand and in the face of pathological challenges, the relative contributions of the various cell cycle regulators in these processes in unknown. (B) Although it is known that the beta-cell compartment harbors extensive regeneration capacity in the face of injury, autoimmune attack and chemical toxins the precise contribution of cell cycle activities in these regeneration processes are unclear. (C) Equally obscure is the transcriptional framework that elicits the regeneration response and importantly the identity of the cellular pool where beta-cell regeneration occurs. (D) Mechanisms of islet growth and the pathways that lead to increase in beta-cell mass are topics of active debate and hence are areas of active investigation. We hypothesize that cell cycle regulators, like Cdk4, play a critical role in development, growth, maintenance and regeneration of the beta cell compartment and we continue to further explore this area of research. Using mouse models, primary cell culture and established cell lines, we are making progress in the above mentioned research areas.
Cell Cycle Regulators in Obesity, Diabetes and Associated Complications
As diabetes and obesity become an overwhelming public health concerns, the cancer risks looming on the horizon are being recognized. A wealth of epidemiological data supports the association between obesity and various types of malignancies. Availability of informative animal models, to address the inter-relationship of obesity with obesity-associated diseases such as diabetes and cancer will have a broad impact on public health of future generations. The studies we are pursuing allow investigation into the role of altered cell cycle progression on obesity, diabetes and cancer. An area that we are actively pursuing is the cell cycle control of adipogenesis. White adipose tissue (WAT) stores energy, whereas brown adipose tissue (BAT) dissipates energy through adaptive thermogenesis. Differentiation of adipocytes requires that growth-arrested preadipocytes reenter the cell cycle before undergoing differentiation. The retinoblastoma (RB) protein acts as a molecular switch determining whether adipocyte differentiation proceeds toward the white or the brown lineage. RB associated E2F transcription factors also play a direct role in the regulation of adipocyte differentiation. Using mouse models and cell culture systems we are pursuing research to delineate upstream and downstream RB/E2F-regulated mechanisms. The ongoing work is helping to elucidate pathways that control white and brown adipose tissue biology in normal physiology and metabolic disease.
TGF-β Superfamily Signaling in Diabetes and Obesity
The transforming growth factor-beta (TGF-β) superfamily, which includes TGF-beta, activin and BMP, has been implicated in pancreatic development and pancreatic diseases. BMP signaling appears to play a role during early pancreatic development and in regulating mature beta-cell function, whereas, activin signaling has been shown to play a role in islet morphogenesis and establishment of beta-cell mass. Our recent observations are consistent with a complex role for TGF-beta signaling in regulation of beta-cell function and we are investigating this in detail. Interestingly, TGF-beta levels are elevated in diabetes, diabetes-associated complications, and obesity. Using mouse models, primary cells, established cell lines and human samples, we are actively studying the role of the TGF-β superfamily in obesity and diabetes.
