Role of Extracellular Matrix in Retinal Development and Disease

细胞外基质在视网膜发育和疾病中的作用

基本信息

批准号：
8512409
负责人：
WILLIAM J BRUNKEN
金额：
$ 9.83万
依托单位：
SUNY DOWNSTATE MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2000
资助国家：
美国
起止时间：
2000-08-01 至 2014-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8512409
关键词：
Address Adherens Junction Adhesions Affect Amacrine Cells American Animals Apical Architecture Basement membrane Blindness Blood Vessels Brain Diseases Cell Adhesion Cell Cycle Cell Polarity Cell Proliferation Cell physiology Cells Cicatrix Collagen Complex Congenital Abnormality Data Defect Dependence Deposition Development Disease Dystroglycan Extracellular Matrix Eye diseases Functional disorder Genes Glaucoma Gliosis Goals Head Health Homeostasis Inner Limiting Membrane Inorganic Sulfates Integrins Ion Channel Knockout Mice Laminin Lateral Lead Left Literature Mediating Mental Retardation Molecular Muller&apos s cell Mus Muscular Dystrophies Neural Retina Pathology Photoreceptors Potassium Channel Process Proliferative Vitreoretinopathy Publishing Regulation Retina Retinal Retinal Defect Retinal Ganglion Cells Role Secondary to Series Site Structure-Activity Relationship Surface Synapses Syndrome Testing Trauma Unspecified or Sulfate Ion Sulfates Vitreous body structure Walkers Work design in vivo malformation migration novel diagnostics novel therapeutics null mutation public health relevance receptor research study scaffold synaptogenesis water channel

项目摘要

DESCRIPTION (provided by applicant): The Muller cells (MCs) have a key role in retinal homeostasis. They are polarized with an apical compartment facing the subretinal space, and a basal surface adhering to the inner limiting membrane (ILM). Disruption of either compartment leads to activation of MCs and pathobiological consequences leading to vision loss. Laminins organize basement membranes (BM), such as the ILM serving as attachment sites for cell adhesion, polarity and proliferation. We produced mice with null mutations in two laminin genes, Lamb2 and Lamc3, and found that these molecules are necessary for normal retinal development. The defects in the Lamb2/c3 nulls include: ILM malformation; MC disorganization; photoreceptor dysgenesis; and progressive pathology in the inner retina. Our long-range goal is to understand the molecular contributions of laminin to the development and stability of MC organization, in particular, as it relates to the functional architecture. Our immediate goal is to assess the organizing hypothesis that MC-laminin interactions are critical for: 1) establishing MC polarity; 2) maintaining MC sub cellular organization and 3) stabilizing the structural integrity of the retina. In Aim 1, we will examine the molecular mechanisms underlying laminin- mediated scaffolding in the MC. We will answer the following three questions. First, we will address: What Is The Molecular Organization Of The Adhesion Complex Of The MC Basal Endfoot? Next, we will determine: What Is The Laminin Dependence Of Ion Channel Sub cellular Localization And Function? Finally, we will investigate: What Is The Mechanism Of Laminin Regulation Of MC Proliferation? In Aim 2, we will examine the corollary hypothesis that the loss of adhesion to laminin substrates disrupts the normal structure/function relationships in the inner retina. Our data show that the Lamb2/c3 null animals have selective disruptions in the IPL. We will answer the following questions. First, we will ask: What Is The Laminin Dependence Of Dendritogenesis In The IPL? Next, we will address: What Are The Mechanisms Of Progressive Retinal Ganglion Cell Loss in Lamb2/Lamc3 nulls? These experiments and the molecular mechanisms they reveal will contribute to our understanding of the pathophysiology of gliosis; proliferative vitreoretinopathy and congenital ocular disorders including Walker-Warburg, Bardet-Biedl, Pierson Syndrome. PUBLIC HEALTH RELEVANCE: Congenital birth defects affect millions of Americans and people world-wide. These diseases include muscular dystrophy, brain and eye disorders leading to mental retardation and blindness. This project investigates the cause of several of these diseases and the results will lead to new diagnostics and therapeutics.

描述（由申请人提供）：Muller 细胞（MC）在视网膜稳态中发挥关键作用。它们通过面向视网膜下腔的顶室和粘附于内界膜（ILM）的基底表面进行偏振。任一区室的破坏都会导致 MC 的激活和导致视力丧失的病理生物学后果。层粘连蛋白组织基底膜 (BM)，例如 ILM，作为细胞粘附、极性和增殖的附着位点。我们培育了两个层粘连蛋白基因 Lamb2 和 Lamc3 无效突变的小鼠，并发现这些分子对于正常视网膜发育是必需的。 Lamb2/c3 nulls 中的缺陷包括： ILM 畸形； MC 组织混乱；光感受器发育不全;以及视网膜内进行性病理学。我们的长期目标是了解层粘连蛋白对 MC 组织的发展和稳定性的分子贡献，特别是因为它与功能结构相关。我们的近期目标是评估组织假设，即 MC-层粘连蛋白相互作用对于以下方面至关重要：1）建立 MC 极性； 2) 维持 MC 亚细胞组织和 3) 稳定视网膜的结构完整性。在目标 1 中，我们将研究 MC 中层粘连蛋白介导的支架的分子机制。我们将回答以下三个问题。首先，我们将讨论：MC 基底端足粘附复合物的分子组织是什么？接下来，我们将确定：离子通道亚细胞定位和功能的层粘连蛋白依赖性是什么？最后，我们将探讨：层粘连蛋白调控MC增殖的机制是什么？在目标 2 中，我们将检查推论假设，即层粘连蛋白基质粘附力的丧失会破坏视网膜内部的正常结构/功能关系。我们的数据显示 Lamb2/c3 无效动物的 IPL 具有选择性破坏。我们将回答以下问题。首先，我们会问：IPL 中树突发生的层粘连蛋白依赖性是什么？接下来，我们将讨论：Lamb2/Lamc3 缺失中进行性视网膜神经节细胞丢失的机制是什么？这些实验及其揭示的分子机制将有助于我们了解神经胶质增生的病理生理学；增殖性玻璃体视网膜病变和先天性眼部疾病，包括 Walker-Warburg、Bardet-Biedl、Pierson 综合征。公共卫生相关性：先天性出生缺陷影响着数百万美国人和全世界人民。这些疾病包括肌肉萎缩症、导致智力低下和失明的脑部和眼部疾病。该项目调查了其中几种疾病的原因，其结果将带来新的诊断和治疗方法。