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.

该子项目是利用 NIH/NCRR 资助的中心拨款提供的资源的众多研究子项目之一。子项目和研究者 (PI) 可能已从另一个 NIH 来源获得主要资金，因此可以在其他 CRISP 条目中得到体现。列出的机构是中心的机构，不一定是研究者的机构。胰岛素是一种肽激素，与其同源细胞表面受体结合，激活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，但其功能尚不清楚。最近，我们报道了磷脂酰肌醇3激酶（PI3K）的p85调节亚基与视网膜杆外节（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。这种相互作用可以通过体内光或体外胰岛素受体的酪氨酸磷酸化来实现。这项通过 ROS 中胰岛素受体的酪氨酸磷酸化将 PI3K 激活联系起来的工作现在为视网膜中这些受体的存在提供了生理学相关性。胰岛素受体的光激活机制及其功能后果尚不清楚，因此需要研究。在该提案中，概述了四个具体目标，这些目标将提供有关视网膜胰岛素受体的基本信息。 1) 检验感光色素和视觉转导级联介导 IRb 光刺激酪氨酸磷酸化的假设。 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) 采用转基因青蛙方法研究视网膜中蛋白质的运动。这些研究的最终目标是了解通过胰岛素受体的光信号传导的生化机制以及下游的生理后果。在此应用中，我们建议采用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。生物学意义延伸到许多视网膜退行性疾病的病因和治疗。