LAMININ IN NEURONAL FUNCTION AND SURVIVAL

层粘连蛋白是一种异源三聚体细胞外基质(ECM)蛋白，参与调节细胞功能和生存的各个方面。我们最近发现，层粘连蛋白在小鼠海马区高表达，这种蛋白的降解可以促进神经元的死亡。在这一应用中，我们建议对层粘连蛋白在中枢神经系统(CNS)中的表达和功能进行系统的探索。具体地说，我们将确定在海马区表达的层粘连蛋白的异构体(S)，确定直接导致其降解的蛋白酶及其切割位置，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，我们将制造出只在海马体中缺乏特定CNS层粘连蛋白亚型的条件性基因敲除小鼠。这些实验将确定哺乳动物中枢神经系统中关键的细胞外基质成分的分子特征和功能作用。

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.