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Role of mTORC1 in Retinal Ganglion Cell Physiology and Disease

mTORC1 在视网膜神经节细胞生理和疾病中的作用

基本信息

批准号：
10229613
负责人：
Steven F Abcouwer
金额：
$ 50.64万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10229613
关键词：
Address Affect Binding Proteins Biological Assay Brain Cause of Death Cell Size Cell Survival Cell physiology Cells Cellular Metabolic Process Cellular Stress Characteristics Clinical Complex DNA Damage Data Dendrites Development Diabetes Mellitus Diabetic Retinopathy Disease Enterobacteria phage P1 Cre recombinase Exhibits FRAP1 gene Functional disorder Ganglion Cell Layer Genes Genetic Translation Glaucoma Goals Growth Growth Factor In Situ Knowledge Label Maintenance Mediating Messenger RNA Metabolic Metabolism Multiprotein Complexes Mus Nerve Degeneration Nerve Fibers Neural Retina Neurons Neuropathy Nutrient Pathway interactions Peptide Initiation Factors Phosphotransferases Physiology Play Predisposition Protein Biosynthesis Proteins Raptors Retina Retinal Diseases Retinal Ganglion Cells RiboTag Role Signal Pathway Signal Transduction Stress Synaptic plasticity Testing Thinness Time Tissues Translating Translations Tuberous sclerosis protein complex Up-Regulation Vision Work adeno-associated viral vector axon guidance base cell growth cell motility cell regeneration conditional knockout diabetic diabetic patient experimental study ganglion cell in vivo inhibitor/antagonist innovation mTOR Inhibitor mTOR inhibition method development negative affect nervous system disorder novel prevent protein expression response retinal neuron translatome

项目摘要

PROJECT SUMMARY This work addresses a fundamental knowledge gap in our understanding of retinal physiology and function that has significant bearing on the early effects of diabetes on the neural retina. Mechanistic target of rapamycin (mTOR) kinase forms the core of two multi-protein complexes: mTOR complex 1 (mTORC1) containing the protein Raptor, and mTORC2 complex containing the protein Rictor. The mTOR signaling network is essential for cellular responses to trophic signals, control of cell metabolism, protein synthesis, cell growth and cell motility. Numerous studies show a key role for mTOR complexes in neuronal function, including axon guidance, dendrite arborization and synaptic plasticity; and numerous neurological disorders are associated with dysfunctions of the mTOR signaling pathway. In contrast, knowledge of the roles of mTOR complexes in retinal physiology and disease is very limited. We propose to test a distinct cell-specific role for mTORC1 in normal retinal ganglion cell (RGC) physiology and to determine if loss of mTORC1 activity is a key contributor to loss of RGC function and viability in diabetes. The proposed study is based on our prior findings that diabetes causes progressive loss of total retinal protein synthesis (Fort, P.E. et al. 2014, Diabetes 63(9):3077-90) and preliminary data showing that: 1) mouse RGC exhibit a high rate of protein synthesis that is dependent upon mTORC1 function, and 2) negating mTORC1 function in the inner retina caused eventual loss of RGC, similar to the neurodegeneration causes by diabetes. mTORC1 activity is required for 5' cap- dependent translation of mRNAs encoding the protein-synthetic machinery. Thus, in Specific Aim 1 we plan to examine the role of mTORC1 activity in RGC protein synthesis and maintenance of RGC function and viability. We will test the hypothesis that loss of mTORC1 function in RGC inhibits translation of a discrete set of mRNAs, eventually leading to a decrease in the general protein synthetic capacity, visual function and viability of RGC. The proposal is also based upon the premise that diabetes causes stress and damage to the neural retina, and RGC in particular. Deactivation of mTORC1 decreases 5' cap-dependent protein translation in response to a number of cellular stresses. Preliminary data also show that diabetes diminishes RGC protein synthesis coinciding with increased expression of the stress-responsive inhibitor of mTORC1 called regulated in development and DNA damage (REDD1). Thus, in Specific Aim 2 we plan to determine if the effects of diabetes on RGC mRNA translation, function and viability are due to lack of mTORC1 activity leading to a reduction in protein synthesis capacity. We will test the hypothesis that maintaining mTORC1 activity and RGC protein translation during diabetes prevents RGC loss and dysfunction. Defining the role of mTORC1 in RGC will greatly increase our knowledge of RGC physiology and of the ways in which diabetes affects the neural retina.

项目概要这项工作解决了我们对视网膜生理学和视网膜生理学理解的基本知识差距功能对糖尿病对神经视网膜的早期影响有重大影响。机械目标雷帕霉素 (mTOR) 激酶形成两种多蛋白复合物的核心：mTOR 复合物 1 (mTORC1) 含有 Raptor 蛋白，以及含有 Rictor 蛋白的 mTORC2 复合物。 mTOR 信号传导网络对于细胞对营养信号的反应、细胞代谢的控制、蛋白质合成、细胞生长和细胞运动。大量研究表明 mTOR 复合物在神经元功能中发挥着关键作用，包括轴突引导、树突分枝和突触可塑性；以及许多神经系统疾病与 mTOR 信号通路功能障碍有关。相比之下，了解 mTOR 的作用视网膜生理学和疾病的复合体非常有限。我们建议测试独特的细胞特异性作用 mTORC1 在正常视网膜神经节细胞 (RGC) 生理学中的作用，并确定 mTORC1 活性丧失是否是关键导致糖尿病患者 RGC 功能和活力丧失。拟议的研究是基于我们之前的发现糖尿病会导致视网膜总蛋白合成逐渐丧失（Fort, P.E. 等人，2014 年，糖尿病 63(9):3077-90) 和初步数据表明：1) 小鼠 RGC 表现出高蛋白质合成率，即依赖于 mTORC1 功能，2) 否定视网膜内 mTORC1 功能导致最终丧失 RGC，类似于糖尿病引起的神经退行性变。 5' 帽需要 mTORC1 活性编码蛋白质合成机制的 mRNA 的依赖翻译。因此，在具体目标 1 中，我们计划检查 mTORC1 活性在 RGC 蛋白质合成和维持 RGC 功能中的作用和生存能力。我们将检验以下假设：RGC 中 mTORC1 功能的丧失会抑制 a 基因的翻译。离散的 mRNA 集，最终导致一般蛋白质合成能力的下降，视觉 RGC 的功能和活力。该提议还基于这样的前提：糖尿病会导致压力和损害神经视网膜，尤其是 RGC。 mTORC1 失活可减少 5' 帽依赖性响应许多细胞应激的蛋白质翻译。初步数据还表明，糖尿病减少 RGC 蛋白合成，同时增加应激反应抑制剂的表达 mTORC1 称为发育和 DNA 损伤调节 (REDD1)。因此，在具体目标 2 中，我们计划确定糖尿病对 RGC mRNA 翻译、功能和活力的影响是否是由于缺乏 mTORC1 活性导致蛋白质合成能力降低。我们将检验以下假设：在糖尿病期间维持 mTORC1 活性和 RGC 蛋白翻译可防止 RGC 损失和功能障碍。定义 mTORC1 在 RGC 中的作用将大大增加我们对 RGC 生理学及其方式的了解其中糖尿病影响神经视网膜。