LAMININ IN NEURONAL FUNCTION AND SURVIVAL

层粘连蛋白在神经元功能和生存中的作用

• 批准号: 6330590
• 负责人: SIDNEY STRICKLAND
• 金额: $ 34.25万
• 依托单位: ROCKEFELLER UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-04-23 至 2003-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6330590
• 关键词: active sites; cytoprotection; enzyme substrate; genetically modified animals; hippocampus; immunocytochemistry; in situ hybridization; kainate; laboratory mouse; laminin; metalloendopeptidases; neural degeneration; neurotrophic factors; plasmin; polymerase chain reaction; protein isoforms; protein metabolism; protein structure function; tissue inhibitor of metalloproteinases

Laminin is a heterotrimeric, extracellular matrix (ECM) protein that has been implicated in mediating various aspects of cell function and survival. We have recently found that laminin is highly expressed in the mouse hippocampus, and that proteolytic degradation of this protein can promote the death of neurons. In this application, we propose a systematic exploration of the expression and function of laminin in the central nervous system (CNS). Specifically, we will determine the isoform(s) of laminin that is expressed in the hippocampus, identify the proteases directly responsible for its degradation and their sites of cleavage, and establish which region of laminin interacts with neurons to promote survival. Armed with this information, we will produce conditional knockout mice that lack the specific CNS laminin isoforms only in the hippocampus. These experiments will define the molecular characteristics and functional role of a critical ECM component in the mammalian CNS.

层粘连蛋白是一种异源三聚体细胞外基质（ECM）蛋白，参与介导细胞功能和存活的各个方面。 我们最近发现层粘连蛋白在小鼠海马中高度表达，并且这种蛋白的蛋白水解降解可以促进神经元的死亡。 在这个应用程序中，我们提出了一个系统的探索层粘连蛋白在中枢神经系统（CNS）的表达和功能。 具体来说，我们将确定在海马中表达的层粘连蛋白的亚型，鉴定直接负责其降解的蛋白酶及其裂解位点，并确定层粘连蛋白的哪个区域与神经元相互作用以促进存活。 有了这些信息，我们将产生只在海马中缺乏特定CNS层粘连蛋白同种型的条件性敲除小鼠。 这些实验将确定哺乳动物CNS中关键ECM组分的分子特征和功能作用。