REGULATION OF METABOLISM BY AKT/PKB IN BETA CELLS AND BRAIN

AKT/PKB 对 β 细胞和大脑代谢的调节

• 批准号: 7215489
• 负责人: Morris Jay Birnbaum
• 金额: $ 30.81万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7215489
• 关键词: biological signal transduction; cell differentiation; cell proliferation; developmental genetics; diabetes mellitus; enzyme activity; genetic regulation; genetically modified animals; histogenesis; laboratory mouse; pancreatic islet function; pancreatic islets; protein kinase

Understanding the regulation of beta cell growth and function is a goal critical to our hopes of achieving rationale therapies for both Type 1 and Type 2 diabetes mellitus. In the former, an autoimmune attack on the islet eliminates beta cells, leading to an absolute, severe deficiency of insulin. One approach to treatment for which there has been some enthusiasm is the experimental expansion of beta cell mass, either in vitro or in vivo. In Type 2 diabetes, increasing insulin resistance, often associated with obesity, boosts the demands on the pancreas for enhanced secretion of insulin. However, the consensus is that this does not become symptomatic until the increased beta cell hyperplasia and insulin secretion can no longer keep pace, and there is a relative deficiency of insulin. Again, it is likely that the disease would be ameliorated considerably by an enhanced increase in functional beta cell mass. A pathway that has received considerable attention in recent years for the control of beta cell growth is the insulin signaling pathway itself. A key intermediate in this pathway is the serine/threonine protein kinase Akt, also known as protein kinase B. This enzyme is activated in a PI 3'-kinase-dependent manner and is now recognized to regulate cell growth, proliferation and differentiation in a number of tissue types. In the previous funding period we showed that overexpression of an active Akt in beta cells leads to a substantial expansion of beta cell mass, caused by an increase in cell number as well as the size of the beta cells. Moreover, animals expressing activated Akt in the beta cells are protected from a number of types of experimental diabetes. In this proposal, we describe experiments aimed at understanding in molecular detail the mechanism by which Akt produces these effects, and clarifying Akt's role in normal beta cell development and the neuronal control of metabolism. The grant is divided into three aims. Aim one is to further manipulate the expression of Akt temporally in the beta cell of the mouse to further clarify the role of the kinase, and to evaluate several downstream signaling molecules. In aim two, we will determine the physiological role of Akt in beta cell growth and function, by selectively ablating the various Akt isoforms in the beta cell. Lastly, in aim 3, we will extend what we have learned about Akt function in the beta cell to explore its role in the control of energy and glucose metabolism by hypothalamic neurons.

了解β细胞生长和功能的调节是我们实现目标的关键 治疗1型和2型糖尿病的基本原理。在前者中，自体免疫攻击 胰岛消除了β细胞，导致绝对严重的胰岛素缺乏。一种方法是 有一些热情的治疗方法也是实验性的扩大β细胞团。 在体外或体内。在2型糖尿病中，胰岛素抵抗的增加通常与肥胖有关，会促进 增加胰岛素分泌对胰腺的需求。然而，人们的共识是，这并不意味着 变得有症状，直到增加的β细胞增殖和胰岛素分泌不再跟上步伐， 而且胰岛素相对不足。同样，这种疾病很可能会得到改善。 显著地通过增强功能β细胞质量的增加。一条已经收到 近年来，控制β细胞生长的相当多的注意力是胰岛素信号通路本身。 该途径中的一个关键中间体是丝氨酸/苏氨酸蛋白激酶Akt，也称为蛋白激酶B。 这种酶是以依赖PI 3‘-激酶的方式被激活的，现在被认为调节细胞生长， 在许多组织类型中的增殖和分化。在上一个资助期，我们展示了 在β细胞中过表达活性Akt会导致β细胞质量的大幅扩张，原因是 细胞数量的增加以及β细胞的大小。此外，表达激活Akt的动物 在β细胞中，细胞受到保护，不受多种实验性糖尿病的影响。在这项提案中，我们 描述旨在从分子细节上了解Akt产生的机制的实验 这些效应，并阐明Akt在正常的β细胞发育和神经元控制中的作用 新陈代谢。这笔赠款分为三个目标。目的一是进一步操纵Akt的表达 以进一步阐明该激酶的作用，并评估几个 下游的信号分子。在第二个目标中，我们将确定Akt在β细胞中的生理作用。 生长和功能，通过选择性地消融β细胞中的各种Akt亚型。最后，在目标3中，我们将 扩展我们已知的Akt在β细胞中的功能，以探索其在能量控制中的作用 和下丘脑神经元的葡萄糖代谢。