Mechanisms of Glucose-Induced Proliferation in Murine Pancreatic beta Cells

描述（由申请人提供）： 该职业发展提案的目的是支持主要研究者，同时她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。该计划概述了一个雄心勃勃但可行的研究计划，以开发胰腺β细胞生长的重要小鼠模型。该计划的关键要素包括优秀导师的支持，新技术的必要培训和教学课程的招生。 糖尿病（DM）是由β细胞质量或功能不足导致的胰岛素缺乏引起的。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。已知β细胞通过增加数量（增殖）和大小（肥大）来补偿增加的胰岛素需求。然而，参与β细胞补偿的机制还没有被很好地理解，无法为此定制药物。这项提案的科学目的是了解更多关于β细胞补偿性生长的调节，以响应一种强有力的刺激，葡萄糖。 培训目标：1）发展候选人对糖尿病和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，实验的成功执行和结果的仔细解释，以及3）学习调查β细胞增殖调节的综合研究议程所需的技术。 研究目的：1）建立葡萄糖诱导的小鼠β细胞代偿模型。使用最先进的技术，我们将在小鼠体内注入葡萄糖，为期4天。之前在大鼠中报道，通过允许对转基因小鼠进行分析，将这种模型应用于小鼠将加速理解β细胞补偿机制的进展。与此同时，培养中葡萄糖诱导的β细胞增殖模型将使我们能够在其他器官的影响之外研究β细胞。2)确定β细胞群是否包含对葡萄糖反应更快复制的亚群。在这里，我们解决的问题，β细胞对生长刺激的反应是如何组织在组织水平：β细胞是一个同质的，缓慢分裂的人口，或者有一个池的祖细胞产生新的β细胞？解决这个问题的实验将在体外进行。3)确定通过IRS2的信号传导在葡萄糖诱导的β细胞代偿中的作用。我们将把我们强大的新模型应用于具有IRS2靶向突变的小鼠，IRS2是一种在其他β细胞补偿模型中至关重要的分子。无论是否需要IRS2，任何一个发现都具有重要意义。

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.