Matrix Metalloproteinases and Regenerative Plasticity Following Brain Injury

每年数以百万计的美国人都是创伤性脑损伤的受害者，这使它成为一种严重的健康问题 挑战。颅脑损伤常涉及严重的轴索损伤，并伴随着神经元的去传入和突触 损失。虽然大脑具有固有的突触重组能力，但这种可塑性在脑外伤后往往会失效， 导致严重的功能缺陷。我们最近研究了细胞外基质(ECM)的作用。 脑创伤后反应性突触发生过程中的蛋白质。我们的结果显示，某些细胞外基质蛋白和 它们的调节性基质金属蛋白酶(MMPs)强烈影响术后恢复的程度 TBI。在这些研究中，我们对比了ECM/MMP在恢复期适应性损伤(单侧)中的反应 皮质内损伤或DEC)和不可恢复的适应不良损伤(液压冲击伤+双侧 内嗅性皮质损伤或TBI+BEC)。两种明胶酶(MMPs 2，9)，基质分解素-1(MMP3)和MMPs 激活型纤溶酶都表现出表达和功能的改变，这与不同时期的 反应性突触发生。我们还发现，基质金属蛋白酶的异常激活与失塑性有关。 在TBI+BEC之后。当应用基质金属蛋白酶抑制剂时，可塑性发生了积极或消极的改变。 取决于给药的时间和损伤的复杂性。鉴于这些结果，我们现在假设具体的 基质酶/底物/效应基团调节突触前和突触后恢复的不同阶段，AS 以及随后损伤后新生突触的稳定。通过对比不同的配置文件 这些基质蛋白在适应性UEC和非适应性TBI+BEC之后，我们将确定个体 突触发生的特定阶段的蛋白质功能障碍可以解释不同程度的恢复。 我们将测试MMP3/集聚蛋白/成纤维细胞生长因子在突触的初始轴突萌发阶段的促进作用 在随后的突触形成过程中，恢复、纤溶酶/磷酸/(3-连环蛋白)和MT-5/基质金属蛋白酶/Ncadherin/ 突触稳定时的A-连环蛋白。在每种情况下，我们都会记录蛋白质和信使核糖核酸的表达， 突触微环境中的分布和结合作用。最后，我们将操纵MMP， 药物抑制或siRNA敲除体内纤溶酶或MT-5-MMPs及其作用的实验研究 使用突触可塑性的结构和生理指标进行恢复。这些研究将更好地定义 基质酶和底物在颅脑损伤诱导的突触可塑性中的作用，并提供新的治疗策略。

Millions of Americans are victims of traumatic brain injury (TBI) every year, making it a serious health challenge. TBI often involves significant axonal injury with attendant neuronal deafferentation and synaptic loss. While the brain has an inherent capacity for synaptic reorganization, this plasticity often fails after TBI, resulting in serious functional deficits. We have recently examined the role of extracellular matrix (ECM) proteins during reactive synaptogenesis induced by TBI. Our results showed that certain ECM proteins and their regulatory matrix metalloproteinases (MMPs) strongly influence the extent of recovery achieved after TBI. In these studies we contrasted ECM/MMP response in a recovering adaptive injury (unilateral entortiinal cortical lesion or DEC) and a non-recovering maladaptive insult (fluid percussion TBI + bilateral entorhinal cortical lesion orTBI+BEC). Two gelatinases (MMPs 2,9), stromelysin-1 (MMP 3) and the MMP activator plasmin all showed shifts in expression and function which correlated with different phases of reactive synaptogenesis. We also found that aberrant MMP activation was associated with failed plasticity after TBI+BEC. When MMP inhibitors were applied, plasticity was altered either positively or negatively depending upon time of dosing and complexity of injury. Given these results, we now posit that specific matrix enzyme/substrate/effector groups mediate the different phases of pre and postsynaptic recovery, as well as the subsequent stabilization of nascent synapses after injury. By contrasting the different profiles of these matrix proteins following adaptive UEC and maladaptive TBI+BEC, we will determine if individual protein dysfunction at specific phases of synaptogenesis can account for the variable extent of recovery. We will test the facilitative role of MMP3/agrin/FGF over the initial axonal sprouting phase of synaptic recovery, plasmin/phosphacan/(3-catenin during the subsequent synaptogenic period, and MT-5MMP/Ncadherin/ a-catenin at synapse stabilization. In each case we will document protein and mRNA expression, distribution in the synapse microenvironment and binding interactions. Finally, we will manipulate MMPS, plasmin or MT-5MMP in vivo by either pharmacological inhibition or siRNA knockdown and test for effect on recovery using structural and physiological indices of synaptic plasticity. These studies will better define matrix enzyme and substrate role in TBI-induced synaptic plasticity and provide new treatment strategies.