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：
7992716
负责人：
WILLIAM J BRUNKEN
金额：
$ 39.75万
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 2013-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7992716
关键词：
Address Adherens Junction Adhesions Affect Amacrine Cells American Animals Apical Architecture Basement membrane Blindness Blood Vessels Brain 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 Therapeutic Trauma Unspecified or Sulfate Ion Sulfates Vitreous body structure Walkers Work design in vivo malformation migration novel diagnostics 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（MCS）在视网膜稳态中具有关键作用。它们具有面向视网膜下空间的顶端隔室的极化，以及粘附在限制膜（ILM）的基底表面。任何一个隔室的破坏都会导致MC的激活和病理生物学后果，从而导致视力丧失。层粘连蛋白组织地下膜（BM），例如用作细胞粘附，极性和增殖的附着位点的ILM。我们在两个层粘连蛋白基因LAMB2和LAMC3中产生了无效突变的小鼠，发现这些分子对于正常的视网膜发育是必需的。 lamb2/c3 nulls中的缺陷包括：ILM畸形； MC混乱；感光细胞失调；和内部视网膜的渐进病理学。我们的远程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，尤其是与功能结构有关的。我们的直接目标是评估MC-Laminin相互作用对以下方式至关重要的组织假设：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AIM 1中，我们将研究MC中层粘连蛋白介导的脚手架的分子机制。我们将回答以下三个问题。首先，我们将解决：MC基底脚足的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，我们将研究：MC增殖的层粘连蛋白调节的机理是什么？在AIM 2中，我们将研究推论假设，即对层粘连蛋白底物的粘附丧失会破坏内部视网膜中正常的结构/功能关系。我们的数据表明，LAMB2/C3无效动物在IPL中有选择性破坏。我们将回答以下问题。首先，我们会问：IPL中树突生成的层粘连蛋白依赖性是什么？接下来，我们将解决：LAMB2/LAMC3 NULLS中进行性视网膜神经节细胞损失的机制是什么？这些实验及其揭示的分子机制将有助于我们对神经胶质病的病理生理学的理解。增生性玻璃体病和先天性眼部疾病，包括Walker-Warburg，Bardet-Biedl，Pierson综合征。公共卫生相关性：先天性先天缺陷会影响数百万美国人和全球人。这些疾病包括肌肉营养不良，大脑和眼睛疾病，导致智力低下和失明。该项目调查了其中几种疾病的原因，结果将导致新的诊断和治疗学。