? The purpose of this career development proposal is to support the Principal Investigator while she acquires the skills and knowledge needed to transition to an academic career in clinically relevant basic science. The program outlines an ambitious but feasible research plan to develop an important mouse model of pancreatic beta cell growth. Critical elements of the plan include the support of excellent mentors, required training in new techniques and enrollment in didactic courses. ? Diabetes mellitus (DM) is caused by insulin deficiency resulting from inadequate beta cell mass or function. In principal, an important class of drugs to treat DM (type 1 or type 2) might include agents that increase the number or effectiveness of beta cells. Beta cells are known to compensate for increased need for insulin by growing in number (proliferation) and size (hypertrophy). However, the mechanisms involved in beta cell compensation aren't understood well enough to tailor medications to this end. The scientific aim of this proposal is to learn more about the regulation of beta cell compensatory growth in response to a potent stimulus, glucose. ? Training aims: 1) To develop the candidate's knowledge of the field of diabetes and beta cell physiology, 2) To build the fundamentals of excellent research, including experimental design, successful execution of experiments, and careful interpretation of results, and 3) To learn techniques required for a comprehensive research agenda investigating the regulation of beta cell proliferation. ? Research aims: 1) To develop and characterize a model of glucose-induced beta cell compensation in mice. Using state-of-the-art technology, we will infuse glucose in mice for a period of 4 days. Previously reported in rats, adapting this model to mice will accelerate progress in understanding the mechanisms of beta cell compensation by allowing analysis of genetically modified mice. In parallel, a model of glucose-induced proliferation of beta cells in culture will allow us to study beta cells outside the influence of other organs. 2) To determine whether the beta cell population contains a subpopulation that replicates more rapidly in response to glucose. Here we address the question of how the beta cell response to a growth stimulus is organized at the tissue level: are beta cells a homogeneous, slowly dividing population, or is there a pool of progenitor cells that produces new beta cells? Experiments to address this question will be performed in vitro. 3) To determine the contribution of signaling through IRS2 in glucose-induced beta cell compensation. We will apply our powerful new model to mice with targeted mutation of IRS2, a molecule shown to be critically important in other models of beta cell compensation. Whether IRS2 is required or not, either finding will be of significant importance. ? ?
