Microglial Phox Activity In Parkinson's Disease

描述(由申请人提供)：小胶质细胞激活和神经炎症的作用最近被认为是帕金森病(PD)发病机制的潜在中介和/或增强剂。虽然导致神经退行性变的确切机制和途径相对不清楚，但已有足够的证据表明，帕金森病的发病机制是多因素的。事实上，环境和遗传因素已被证明引起小胶质细胞的激活，导致神经炎症和随后对黑质纹状体多巴胺系统的损害。此外，遗传和环境伤害都涉及NADPH氧化酶(PHOX)的激活，这是小胶质细胞激活后神经毒性反应的关键中介。这些数据突显了PHOX的重要性，并在帕金森病的发展过程中提供了遗传易感性和环境侮辱之间的共同联系。因此，这项建议将利用PHOX的遗传和环境因素的交集来更好地了解小胶质细胞介导的神经毒性的机制。通过利用体外和体内模型，提出的AIMS将系统地阐明内源性和外源性INS之间的相互作用以及它们在小胶质细胞激活和神经变性中的协同作用。此外，还将研究参与这些过程的特定相互作用蛋白和途径，这些结果将在帕金森病患者的人体组织中得到进一步验证，并与其他神经退行性疾病进行比较。这些拟议目标的完成将有助于更好地了解PHOX遗传因素和环境因素之间的相互作用。最后，识别参与小胶质细胞介导的神经变性的特定蛋白质和通路可能为帕金森病患者提供潜在的治疗干预靶点。

DESCRIPTION (provided by applicant): The role of microglial activation and neuroinflammation has recently emerged as a potential mediator and /or potentiator of Parkinson's disease (PD) pathogenesis. While the precise mechanisms and pathways responsible for neurodegeneration are relatively unclear, sufficient evidence has been put forth to suggest that PD has a multifactorial etiopathogenesis. Indeed, environmental as well as genetic factors have been demonstrated to cause activation of microglia, leading to neuroinflammation and subsequent damage to the nigrostriatal dopamine system. Furthermore, genetic and environmental insults both involve activation of NADPH oxidase (PHOX), a key mediator of the neurotoxic response following microglial activation. These data highlight the importance of PHOX and provides a common link between genetic susceptibility and environmental insult in the development of PD. Thus, this proposal will exploit the intersection of genetic and environmental factors at PHOX to gain a better understanding of the mechanisms involved in microglia- mediated neurotoxicity. Through the utilization of in vitro and in vivo models, the aims proposed will systematically elucidate the interplay between endogenous and exogenous insults and their synergistic contribution to microglial activation and neurodegeneration. Moreover, specific interacting proteins and pathways involved in these processes will be examined and these results will be further validated in human tissue from PD patients and compared to other neurodegenerative diseases. Completion of these proposed aims will provide a better understanding of the interaction of genetic and environmental factors at PHOX. Finally, the identification of specific proteins and pathways involved in microglia-mediated neurodegeneration may provide potential targets of therapeutic intervention for patients with PD.