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: 7486269
• 负责人: Morris Jay Birnbaum
• 金额: $ 30.76万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7486269
• 关键词: 1-Phosphatidylinositol 3-Kinase; Animals; Apoptosis; Attention; Autoimmune Process; Beta Cell; Biochemical; Brain; Cell Count; Cessation of life; Consensus; Coupling; Data; Diabetes Mellitus; Disease; Enzymes; Equilibrium; Event; Experimental Diabetes Mellitus; Funding; Genes; Goals; Grant; Growth; Hand; Histocompatibility Testing; Hyperplasia; Hypothalamic structure; In Vitro; Insulin; Insulin Resistance; Insulin Signaling Pathway; Insulin-Like Growth Factor Binding Protein 5; Insulin-Like Growth Factor I; Islets of Langerhans; Knock-out; Learning; Metabolism; Molecular; Mus; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Numbers; Obesity; Pancreas; Pathway interactions; Personal Satisfaction; Phosphatidylinositols; Phosphotransferases; Physiological; Process; Protein Isoforms; Protein Overexpression; Protein-Serine-Threonine Kinases; Proteins; Proto-Oncogene Proteins c-akt; Regulation; Relative (related person); Research Design; Role; Signal Pathway; Signal Transduction; Signaling Molecule; Stimulus; Stress; Structure of beta Cell of islet; base; cell growth; cyclin G; energy balance; forkhead protein; glucose metabolism; in vivo; inhibitor/antagonist; insulin receptor substrate 1 protein; insulin secretion; interest; islet; research study; size; transcription factor; type I and type II diabetes

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对于我们实现的希望至关重要 1型和2型糖尿病的理性疗法。在前者中，对自身免疫性攻击 胰岛消除了β细胞，导致绝对严重的胰岛素缺乏。一种方法 具有某种热情的治疗是β细胞量的实验扩展，要么 体外或体内。在2型糖尿病中，增加胰岛素抵抗（通常与肥胖有关）可以提高 对胰腺增强胰岛素分泌的需求。但是，共识是这不是 成为症状性，直到增加的β细胞增生和胰岛素分泌无法再跟上步伐， 并且存在相对缺乏胰岛素。同样，这种疾病可能会得到改善 功能性β细胞量的增加大大增加了。收到的途径 近年来，控制β细胞生长的关注是胰岛素信号通路本身。 该途径中的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。 该酶以Pi 3'-激酶依赖性的方式被激活，现在被识别为调节细胞生长， 多种组织类型的增殖和分化。在上一个资金期间，我们表明 β细胞中活性AKT的过表达导致β细胞量的大量扩展，这是由 细胞数以及β细胞的大小增加。此外，表达激活AKT的动物 在β细胞中，可以保护多种类型的实验性糖尿病。在这个建议中，我们 描述旨在以分子细节理解AKT产生的机制的实验 这些影响，并阐明AKT在正常β细胞发育中的作用以及 代谢。赠款分为三个目标。目的是进一步操纵AKT的表达 在小鼠的β细胞中暂时以进一步阐明激酶的作用，并评估几个 下游信号分子。在目标二，我们将确定AKT在β细胞中的生理作用 生长和功能，通过选择性地烧毁β细胞中的各种AKT同工型。最后，在AIM 3中，我们将 扩展我们在β单元中了解AKT功能的知识，以探索其在能量控制中的作用 下丘脑神经元的葡萄糖代谢。