Reactive Microgliosis and Progressive Dopaminergic Neurotoxicity

帕金森氏病（PD）是一种破坏性的运动障碍，其特征在于进行性的 黑质中的多巴胺能（DA）神经元，其中DA神经元损失的机制很差 明白虽然PD影响大约1.5%的北美人口，但现有的治疗方法 仅能暂时改善PD症状，不能延缓疾病进展。大多数PD病例 是散发性的，环境毒物与PD病因有关。小胶质细胞， 大脑，被认为有助于PD的进行性。小胶质细胞在DA 神经元损伤导致炎症和邻近DA神经元的损伤（反应性小胶质细胞增生），但 其机制在很大程度上尚不清楚。在这里，我们解决过度假设， 可溶性神经元损伤因子在环境损伤（MPP+/MPTP）时释放，以促进小胶质细胞 激活，这进一步驱动DA神经毒性，导致恶性的，自我推进的循环。本研究 专注于u钙蛋白酶，一种细胞内钙依赖性蛋白酶，据报道， 在皮层神经元损伤时细胞外。使用体外/体内组合方法，我们将测试 特异性假设，u钙蛋白酶是DA神经元损伤后释放的关键可溶性因子， MPP+/MPTP激活小胶质细胞，然后增强额外的DA神经毒性。的具体目标 该建议是：1）确定可溶性因子的促炎和神经毒性特征 从暴露于直接神经毒性剂MPP+的DA神经元释放（指导阶段）; 2）表征 钙蛋白酶作为可溶性神经元损伤因子，促进反应性小胶质细胞增生（独立期）; 3） 描述了MAC 1受体介导的u钙蛋白酶诱导的小胶质细胞活化和DA的机制。 神经毒性（独立期）; 4）确定u钙蛋白酶对进行性 神经退行性变，体外和体内MPTP小鼠模型（独立阶段）。拟议 研究将揭示驱动自我推进神经退行性变的新分子信号， 具有减缓PD进展潜力的治疗靶点。此外，这项研究将建立 为进一步研究环境因素促进反应性 小神经胶质增生、进行性神经毒性和PD。

Parkinson's disease (PD) is a devastating movement disorder characterized by the progressive loss of dopaminergic (DA) neurons in the substantia nigra, where mechanisms of DA neuron loss are poorly understood. While PD affects approximately 1.5% of the North American population, available treatments only temporarily ameliorate PD symptoms and can not slow disease progression. The majority of PD cases are sporadic and environmental toxicants are linked to PD etiology. Microglia, the resident macrophage in the brain, are believed to contribute to the progressive nature of PD. Microglia are activated upon DA neuron injury to result in inflammation and damage to neighboring DA neurons (reactive microgliosis), but the mechanisms responsible are largely unknown. Here, we address the over-arching hypothesis that soluble neuron-injury factors are released upon environmental insult (MPP+/MPTP) to promote microglial activation, which drives further DA neurotoxicity, to result in a vicious, self-propelling cycle. This study is focused on u calpain, an intracellular calcium-dependant protease that is reported to be released extracellularly upon cortical neuron damage. Using a combined in vitro/in vivo approach, we will test the specific hypothesis that u calpain is a key soluble factor released upon DA neuron damage with MPP+/MPTP to activate microglia, which then potentiates additional DA neurotoxicity. The specific aims of this proposal are to: 1) determine the pro-inflammatory and neurotoxic characteristics of soluble factors released from DA neurons exposed to the direct neurotoxicant MPP+ (Mentored Phase); 2) characterize u calpain as a soluble neuron-injury factor contributing to reactive microgliosis (Independent Phase); 3) characterize the MAC1 receptor-mediated mechanism of u calpain-induced microglia activation and DA neurotoxicity (Independent Phase); 4) define the enhancing action of u calpain on progressive neurodegeneration, both in vitro and in an in vivo MPTP mouse model (Independent Phase). The proposed studies will reveal novel molecular signals that drive self-propelling neurodegeneration and identify therapeutic targets with the potential to slow PD progression. Additionally, this research will establish the groundwork for further studies into the mechanisms by which environmental factors contribute to reactive microgliosis, progressive neurotoxicity, and PD.