MMPs in neural networking

描述（由申请人提供）：证据表明整合素可能对神经元网络的建立和维持至关重要。整合素参与了神经元的定向迁移及其过程，许多研究表明它们也参与了突触的稳定。整合素在神经网络中发挥作用的能力受到整合素结合配体的性质和可用性的影响。这些配体包括细胞表面受体、信号素等可溶性分子和细胞外基质（ECM）的精选蛋白质。最近的研究表明，在中枢神经系统（CNS）炎症的情况下，神经网络和整合素结合配体的可用性都可能发生改变。例如，在猿猴免疫缺陷病毒脑炎（SIVE）中，突触损伤和神经元周围基质的丢失已被证实。同样，在人类免疫缺陷性痴呆中，树突乔木的丢失也被观察到。至于在发育过程中可能发生的变化，子宫内巨细胞病毒感染与皮层组织破坏有关。虽然多种机制可能导致炎症背景下的神经网络紊乱，但基质金属蛋白酶（MMP）介导的整合素功能变化可能发挥重要作用。MMPs降解已知与整合素相互作用的ECM成分，并且选择性MMPs也被证明与细胞表面整合素直接相关。在目前的提议中，我们概述了测试MMPs会干扰神经元迁移和突触形成或维持的假设的计划。我们还将检验这种效应依赖于神经元整合素的假设。我们的研究结果应该提高我们对那些以MMPs水平升高为特征的中枢神经系统炎症性疾病的理解。

DESCRIPTION (provided by applicant): Evidence suggests that integrins may be critical to the establishment and maintenance of neuronal networks. Integrins are involved in the directed migration of both neurons and their processes, and a number of studies suggest they are also involved in the stabilization of synapses. The ability of integrins to play a role in neural networking is understandably influenced by the nature and availability of integrin binding ligands. These ligands include cell surface receptors, soluble molecules such as the semaphorins, and select proteins of the extracellular matrix (ECM). Recent studies have shown that both neural networking and the availability of integrin binding ligands may be altered in the setting of central nervous system (CNS) inflammation. For example, in simian immunodeficiency virus encephalitis (SIVE), synaptic damage and loss of perineuronal matrix has been demonstrated. Similarly, in human immunodeficiency dementia, a loss of dendritic arbor has been observed. And with respect to changes that may occur in development, in utero infection with cytomegalovirus has been linked to disrupted cortical organization. While multiple mechanisms are likely to contribute to disordered neural networking in the context of inflammation, matrix metalloproteinase (MMP) mediated changes in integrin function are likely to play an important role. MMPs degrade constituents of the ECM that are known to interact with integrins, and select MMPs have also been shown to directly associate with cell surface integrins. In the present proposal, we outline plans to test the hypothesis that MMPs will interfere with neuronal migration and with the formation or maintenance of synapses. We will also test the hypothesis that such effects are dependent on neuronal integrins. The results of our studies should improve our understanding of those CNS inflammatory diseases that are characterized by elevated levels of MMPs.