Mechanisms of Glucose-Induced Proliferation in Murine Pancreatic beta Cells

描述(由申请人提供)： 这项职业发展建议的目的是在首席研究员获得过渡到临床相关基础科学学术生涯所需的技能和知识的同时，为她提供支持。该计划勾勒出一项雄心勃勃但可行的研究计划，旨在开发一种重要的胰岛β细胞生长小鼠模型。该计划的关键要素包括优秀导师的支持、必要的新技术培训以及参加教学课程。 糖尿病(DM)是由于胰岛β细胞质量或功能不足而导致的胰岛素缺乏。原则上，治疗糖尿病(1型或2型)的一类重要药物可能包括增加β细胞数量或有效性的药物。众所周知，β细胞通过在数量(增殖)和大小(肥大)上的增长来弥补对胰岛素需求的增加。然而，涉及β细胞补偿的机制还不够清楚，无法为此量身定做药物。这项提议的科学目的是了解更多关于β细胞补偿生长的调控，以应对强有力的刺激--葡萄糖。 培训目标：1)发展候选人在糖尿病和β细胞生理学领域的知识，2)建立优秀研究的基础，包括实验设计、成功执行实验和仔细解释结果，以及3)学习研究β细胞增殖调节的全面研究议程所需的技术。 研究目的：1)建立和鉴定葡萄糖诱导的小鼠胰岛β细胞代偿模型。使用最先进的技术，我们将给小鼠输注葡萄糖，为期4天。先前在大鼠中报道，通过对转基因小鼠进行分析，使这个模型适应小鼠，将加速理解β细胞补偿机制的进展。同时，葡萄糖诱导培养中的β细胞增殖的模型将使我们能够研究其他器官以外的β细胞的影响。2)确定β细胞群是否包含对葡萄糖反应更快的复制亚群。在这里，我们讨论了β细胞对生长刺激的反应是如何在组织水平上组织的问题：β细胞是一个同质的、缓慢分裂的群体，还是存在产生新的β细胞的祖细胞池？解决这个问题的实验将在体外进行。3)确定IRS2信号在葡萄糖诱导的β细胞代偿中的作用。我们将把我们强大的新模型应用于IRS2靶向突变的小鼠，这种分子被证明在其他β细胞代偿模型中至关重要。无论是否需要IRS2，这两个发现都将具有重要意义。

DESCRIPTION (provided by applicant): 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.