MMP-7 and SNARE Cleavage in Neuroinflammation

描述（由申请人提供）：多种炎症性疾病通过过度蛋白水解诱导组织损伤。然而，神经元底物的蛋白水解在多大程度上可以促进脑病理学是不太清楚。蛋白水解酶的一个特别重要的家族是基质金属蛋白酶（MMP），锌依赖性分泌的内肽酶，其可以切割细胞外基质蛋白以及细胞因子和细胞表面受体。MMP在脑内产生，并且它们的产生可通过促炎细胞因子和β 2-淀粉样蛋白增加。此外，在阿尔茨海默病、血管性痴呆和HIV相关性痴呆中已经报道了MMPs的表达升高。虽然一些研究已经研究了MMPs具有神经毒性的可能性，但缺乏对这些酶水平升高如何影响神经元生理学的充分理解。特别重要的是MMPs通过对突触的作用来影响神经元网络的潜力。初步数据显示，至少一种MMP，MMP-7在体外抑制突触囊泡释放。这些数据还表明，已知在突触囊泡释放中起作用的选择SNARE蛋白的免疫反应性被外源性MMP-7降低。本发明的中心假设是MMP-7通过SNARE蛋白的直接突触内切割改变突触囊泡释放。将检查MMP-7通过内吞作用进入神经元，然后介导必需SNARE蛋白的突触内裂解的可能性。该研究的基本原理是，如果MMP-7对突触结构和功能有直接影响，则可能导致CNS炎症背景下的突触功能障碍，并且过量的蛋白水解可能被认为是神经保护治疗的靶点。该应用程序的目的是了解MMP-7，一种在大脑炎症中水平增加的蛋白酶，如何影响神经元与神经元的通信。这项研究与公共卫生的相关性在于，它可以解释炎症如何导致神经功能障碍。选择蛋白酶的过量水平可以被认为是神经保护药物的新靶点。

DESCRIPTION (provided by applicant): A variety of inflammatory conditions induce tissue damage through excess proteolysis. However, the extent to which proteolysis of neuronal substrates can contribute to brain pathology is less well understood. A particularly important family of proteolytic enzymes is the matrix metalloproteinases (MMPs), zinc- dependent, secreted endopeptidases that can cleave extracellular matrix proteins as well as cytokines and cell surface receptors. MMPs are produced within the brain and their production may be increased by pro-inflammatory cytokines and 2-amyloid. Moreover, elevated expression of MMPs has been reported in Alzheimer's disease, vascular dementia, and HIV-associated dementia. While some studies have examined the possibility that MMPs are neurotoxic, a full understanding of how elevated levels of these enzymes may influence neuronal physiology is lacking. Of particular importance is the potential for MMPs to influence neuronal networks via an effect on the synapse. Preliminary data shows that at least one MMP, MMP-7 inhibits synaptic vesicle release in vitro. Such data also shows that immunoreactivity for select SNARE protein, known to play a role in synaptic vesicle release, is reduced by exogenous MMP-7. The central hypothesis of the present proposal is that MMP-7 alters synaptic vesicle release via direct intrasynaptic cleavage of SNARE protein(s). The possibility that MMP-7 enters neurons via endocytosis and then mediates intrasynaptic cleavage of essential SNARE protein(s) will be examined. The rationale for the research is that if MMP-7 has direct effects on synaptic structure and function, it may contribute to synaptic dysfunction in the setting of CNS inflammation, and excess proteolysis may be considered as a target for neuroprotective therapeutics. The purpose of the application is to understand how MMP-7, a protease whose levels are increased in the brain inflammations, influences neuron to neuron communication. The relevance of this research to Public Health is that it may explain how inflammation contributes to neurological dysfunction. Excess levels of select proteases may be considered as novel targets for neuro-protective drugs.