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。整合素参与神经元及其过程的定向迁移，许多研究表明它们也参与突触的稳定。整合素在神经网络中发挥作用的能力可以理解地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、可溶性分子如脑信号蛋白和细胞外基质（ECM）的选择蛋白。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，在猴免疫缺陷病毒性脑炎（SIVE）中，已经证实了突触损伤和神经元周围基质的丢失。类似地，在人类免疫缺陷性痴呆中，已经观察到树突状乔木的损失。关于发育过程中可能发生的变化，子宫内巨细胞病毒感染与皮质组织的破坏有关。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。MMP降解已知与整联蛋白相互作用的ECM组分，并且选择的MMP也已显示与细胞表面整联蛋白直接缔合。在目前的建议中，我们概述了计划来测试的假设，基质金属蛋白酶将干扰神经元迁移和突触的形成或维持。我们还将测试的假设，这种影响是依赖于神经元整合素。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CNS炎性疾病的理解。

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.