Neuroprotection Mechanism for Photoreceptors

光感受器的神经保护机制

基本信息

批准号：
10006824
负责人：
Raju VS Rajala
金额：
$ 42.27万
依托单位：
UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-30 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10006824
关键词：
1p36 Address Adult Affect Age related macular degeneration Binding Biochemical Biological Biological Availability Blindness Cell Death Cell physiology Cell surface Cells Cellular biology Chromosomes Defect Etiology Event Eye Failure Family member Foundations Future GRB14 gene Gene Expression Goals Growth Growth Factor Half-Life Human Insulin-Like Growth Factor I Insulin-Like Growth-Factor-Binding Proteins Insulin-Like-Growth Factor I Receptor Knock-out Knockout Mice Laboratories Lead Leber&apos s amaurosis Length Ligands Light Literature Liver Maintenance Mediating Mental Retardation Methods Microcephaly Mitochondria Mitotic Molecular Muller&apos s cell Mus Mutation Nucleotide Biosynthesis Outcome PTK6 gene Pathway interactions Patients Pharmacology Pharmacotherapy Phosphoric Monoester Hydrolases Phosphorylation Photoreceptors Process Property Protein Biosynthesis Protein Dephosphorylation Protein Inhibition Protein Tyrosine Kinase Protein phosphatase Proteins Receptor Activation Receptor Inhibition Receptor Signaling Regulation Reporting Research Retina Retinal Cone Retinal Degeneration Retinal Diseases Retinitis Pigmentosa Rod Role Signal Pathway Signal Transduction Signaling Molecule Source Stress Structure Testing Tissues Up-Regulation Usher Syndrome Vision Work age related blind cell growth regulation congenital deafness deafness disease phenotype early onset extracellular innovation inorganic phosphate insulin regulation lipid biosynthesis neoplastic cell neuroprotection neurotrophic factor novel photoreceptor degeneration postnatal preservation prevent protein activation protein tyrosine phosphatase 1B receptor receptor function receptor-mediated signaling response retinal rods solute translational impact

项目摘要

PROJECT SUMMARY/ABSTRACT Signal transduction occurs when an extracellular signaling molecule activates a specific receptor located on the cell surface or inside the cell. In turn, this receptor triggers a biochemical chain of events inside the cell, creating a response. The signaling network mediated by insulin-like growth factor 1 (IGF-1) receptor is fundamentally important for the regulation of a number of cellular functions, including the neuroprotection of post-mitotic cells. The specific objectives of this application are to investigate the mechanism of IGF-1R- mediated signaling in both rod and cone photoreceptors, and the regulation of the cellular processes required to promote and sustain photoreceptor functionality and viability. The research strategy outlined in this proposal is built upon the recently uncovered function of IGF-1R in photoreceptor neuroprotection, and a fundamental property of IGF-1R in many other cell tissues. The study proposed herein will define how IGF-1R regulates photoreceptor functions. Using genetically modified mice and pharmacological agents, we have identified changes in cellular signaling and gene expression in the retina. We have identified several activators and negative regulators of IGF-1R signaling in the retina, and have developed methods for manipulating IGF-1R activation to detect the impact on photoreceptor functions. We will use these methods to determine how IGF-1R signaling regulates photoreceptor neuroprotection and other cellular functions. We will study the source of IGF-1 to activate IGF-1R and the consequence of its absence in rods (Aim 1). We will test the mechanisms of IGF-1R activation and deactivation in the retina (Aim 2). Successful completion of our studies could benefit millions of people who are blind from rod and cone cell loss. Our new and innovative approaches will facilitate future translational application of our work, with the goal of applying our findings to the treatment of human retinal degenerations. Elucidating these mechanisms is critical to advancing our understanding of basic photoreceptor cell biology and pathobiological mechanisms underlying the photoreceptor degeneration that is frequently associated with defects in anabolic processes.

项目概要/摘要当细胞外信号分子激活位于细胞上的特定受体时，就会发生信号转导细胞表面或细胞内部。反过来，这种受体会触发细胞内的一系列生化事件，创建响应。由胰岛素样生长因子 1 (IGF-1) 受体介导的信号网络是对于许多细胞功能的调节至关重要，包括神经保护有丝分裂后细胞。本申请的具体目标是研究 IGF-1R-的机制视杆细胞和视锥细胞光感受器介导的信号传导，以及所需细胞过程的调节促进和维持光感受器的功能和活力。本提案中概述的研究策略是建立在最近发现的 IGF-1R 在光感受器神经保护作用，也是许多其他细胞组织中 IGF-1R 的基本特性。研究本文提出的将定义 IGF-1R 如何调节光感受器功能。使用转基因小鼠和药物制剂，我们已经确定了细胞信号传导和基因表达的变化视网膜。我们已经确定了视网膜中 IGF-1R 信号传导的几种激活剂和负调节剂，并且开发了操纵 IGF-1R 激活的方法，以检测对感光功能的影响。我们将使用这些方法来确定 IGF-1R 信号如何调节光感受器神经保护和其他细胞功能。我们将研究IGF-1的来源激活IGF-1R及其后果视杆细胞缺失（目标 1）。我们将测试视网膜中 IGF-1R 激活和失活的机制（目标 2）。我们的研究的成功完成可以使数以百万计因视杆细胞和视锥细胞丧失而失明的人受益。我们的新方法和创新方法将促进我们工作的未来转化应用，目标是将我们的研究结果应用于人类视网膜变性的治疗。阐明这些机制至关重要增进我们对基本感光细胞生物学和病理生物学机制的理解光感受器变性通常与合成代谢过程的缺陷相关。