COBRE: INSULIN RECEPTOR SIGNALING IN RETINA

COBRE：视网膜中的胰岛素受体信号传导

• 批准号: 7381939
• 负责人: Raju VS Rajala
• 金额: $ 19.31万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 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 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7381939
• 关键词: COBRE; INSULIN; RECEPTOR; SIGNALING; RETINA

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Insulin, a peptide hormone binds its cognate cell surface receptors to activate a coordinated biochemical-signaling network and induce intracellular events. The retina is an integral part of the central nervous system and is known to contain insulin receptors, although their function is not known. Recently, we have reported that the p85 regulatory subunit of phosphatidylinositol 3-kinase (PI3K) interacts directly with the insulin receptor-beta subunit (IRb) in retinal rod outer segments (ROS), which leads to activation of the PI3K enzyme. This interaction can be achieved either by light in vivo or through tyrosine phosphorylation of insulin receptor in vitro. This work linking PI3K activation through tyrosine phosphorylation of the insulin receptor in ROS now provides physiological relevance for the presence of these receptors in the retina. The mechanism of light activation of the insulin receptor and the functional consequences are unknown and therefore need to be investigated. In this proposal, four specific aims are outlined that will provide fundamental information on insulin receptors in the retina. 1) To test the hypothesis that photopigments and the visual transduction cascade mediate the light-stimulated tyrosine phosphorylation of the IRb. 2) To elucidate the mechanism of light-stimulated tyrosine phosphorylation of the IRb. 3) To determine the role of insulin binding protein Grbl0 in the regulation of the IRb. 4) To employ transgenic frog approach to study the movement of proteins in retina. These studies are being undertaken with the ultimate goal of understanding the biochemical mechanism of light signaling through the insulin receptor and the downstream physiological consequences. In this application, we propose to study the mechanism of light activation of insulin receptor employing various transgenic and knockout mouse models, biochemical, and molecular and immunological experiments. Our long-term goal is to understand the role of insulin receptors in the retina and elucidate the intracellular signaling pathways they generate. The biological implication extends to the cause and treatment of a number of retinal degenerative diseases.

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。胰岛素是一种多肽激素，它与其同源细胞表面受体结合，激活一个协调的生化信号网络，并诱导细胞内事件。视网膜是中枢神经系统的组成部分，已知含有胰岛素受体，尽管它们的功能尚不清楚。最近，我们报道了磷脂酰肌醇3-激酶(PI3K)的P85调节亚基与视网膜视杆细胞外节(ROS)中的胰岛素受体-β亚基(IRB)直接相互作用，从而导致PI3K酶的激活。这种相互作用既可以通过体内的光，也可以通过体外胰岛素受体的酪氨酸磷酸化来实现。这项工作通过ROS中胰岛素受体的酪氨酸磷酸化将PI3K激活联系在一起，现在为这些受体在视网膜中的存在提供了生理上的关联。光激活胰岛素受体的机制和功能后果尚不清楚，因此需要进行研究。在这项提案中，概述了四个特定的目标，将提供关于视网膜中胰岛素受体的基本信息。1)验证感光色素和视觉转导级联介导光刺激IRB酪氨酸磷酸化的假说。2)阐明光刺激IRB酪氨酸磷酸化的机制。3)确定胰岛素结合蛋白Grbl0在IRB调节中的作用。4)用转基因青蛙方法研究蛋白质在视网膜中的运动。这些研究的最终目的是通过胰岛素受体了解光信号的生化机制及其下游的生理后果。在这一应用中，我们建议通过各种转基因和基因敲除小鼠模型、生化以及分子和免疫学实验来研究胰岛素受体的光激活机制。我们的长期目标是了解胰岛素受体在视网膜中的作用，并阐明它们产生的细胞内信号通路。这一生物学意义延伸到许多视网膜退行性疾病的病因和治疗。