Proteasome Function in the Aging Retina

蛋白酶体在老化视网膜中的功能

基本信息

批准号：
7895515
负责人：
Deborah Ann Ferrington
金额：
$ 36.81万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-09-15 至 2011-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7895515
关键词：
Age Aging Alzheimer&apos s Disease American Antigen Presentation Bone Marrow Brain CD8B1 gene Catalytic Domain Cell Cycle Regulation Cell Survival Cells Chronic Complex Cultured Cells Dependence Development Disease Elements Equilibrium Exhibits Exposure to Funding Gene Expression Health Homeostasis Immune system Injury Light Link Lipids Maintenance Malignant Neoplasms Measures Mediating Methyl Green Modeling Morphology Mus Natural regeneration Nerve Crush Neurodegenerative Disorders Optic Nerve Oxidative Stress Oxygen Parkinson Disease Pathway interactions Peptides Play Predisposition Process Production Proteins Proteolysis Proteome Proteomics Quality Control Recovery Regulation Retina Retinal Role Signal Transduction Spleen Stress T-Lymphocyte Testing Therapeutic Intervention Tissues Transduction Gene Work adverse outcome base biological adaptation to stress copper zinc superoxide dismutase experience ganglion cell in vivo injury and repair multicatalytic endopeptidase complex protein degradation protein misfolding repaired research study response retinal damage sodium iodate

项目摘要

This application is in response to potential support for two years as part of the American Recovery and Reinvestment Act of 2009. The Specific Aims have been modified from the original proposal to fit 2 years of funding. The proteasome complex plays a fundamental role in processes essential for cell viability, such as cell cycle regulation, control of signal transduction and gene expression, and the degradation of oxidized and misfolded proteins. Two types of proteasomes, the constitutive and immunoproteasomes, have been described. The proposed work investigates factors that influence the balance between the two proteasome subtypes in cells of the retina, and tests specific hypotheses regarding the dependence of retinal homeostasis on immunoproteasome function. The underlying hypothesis is that immunoproteasome performs functions that are vital to cells under stress; this hypothesis links the immunoproteasome to the innate immune system, and its role in tissue homeostasis, but does not limit it to immunological functions. Aim 1 tests the hypothesis that immunoproteasome is critical for maintaining a healthy retina under normal conditions in vivo. The approach is to use immunoproteasome-deficient mice lacking two (lmp7/-/mecl-r/-) catalytic subunits of immunoproteasome (L7Ml mice) to determine the consequences of inhibiting immunoproteasome expression by comparing age-matched WT and L7Ml mice, ages 1 to 24 months. Aim 2 tests the hypothesis that the inability to make immunoproteasome sensitizes the retina to more adverse outcomes following extraordinary stress. The extent of damage in WT and L7Ml mice after two distinct types of injury models (constant light and optic nerve crush) will be tested. Results from these experiments will help verify that immunoproteasome is an essential component of the retinal stress response and plays a fundamental role in maintaining retinal health.

此申请是为了响应 2009 年《美国复苏和再投资法案》中可能提供的两年资助。具体目标已对最初的提案进行了修改，以适应 2 年的资助。蛋白酶体复合物在细胞活力所必需的过程中发挥着重要作用，例如细胞周期调节、信号转导和基因表达的控制以及氧化和错误折叠蛋白质的降解。已经描述了两种类型的蛋白酶体，即组成型蛋白酶体和免疫蛋白酶体。拟议的工作研究了影响视网膜细胞中两种蛋白酶体亚型之间平衡的因素，并测试了有关视网膜稳态对免疫蛋白酶体功能依赖性的具体假设。基本假设是免疫蛋白酶体执行以下功能：对处于压力下的细胞至关重要；该假说将免疫蛋白酶体与先天免疫系统及其在组织稳态中的作用联系起来，但并不限于免疫功能。目标 1 检验免疫蛋白酶体对于体内正常条件下维持健康视网膜至关重要的假设。该方法是使用缺乏免疫蛋白酶体的两个(lmp7/-/mecl-r/-)催化亚基的免疫蛋白酶体缺陷型小鼠(L7M1小鼠)，通过比较年龄匹配的WT和L7M1小鼠(1岁)来确定抑制免疫蛋白酶体表达的后果。至 24 个月。目标 2 检验了这样的假设：无法产生免疫蛋白酶体会使视网膜在承受巨大压力后对更不利的结果变得敏感。两种不同类型的损伤模型（恒定光和强光照射）后WT和L7M1小鼠的损伤程度视神经挤压）将进行测试。这些实验的结果将有助于验证免疫蛋白酶体是视网膜应激反应的重要组成部分，并在维持视网膜健康方面发挥着重要作用。