Microglial Phox Activity In Parkinson's Disease

描述（由申请人提供）：小胶质细胞活化和神经炎症的作用最近已成为帕金森病（PD）发病机制的潜在介质和/或增效剂。虽然负责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PD具有多因素的发病机制。事实上，环境和遗传因素已被证明会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，遗传和环境损伤都涉及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介质。这些数据突出了PHOX的重要性，并提供了遗传易感性和PD发展中的环境损伤之间的共同联系。因此，该提议将利用PHOX的遗传和环境因素的交叉点，以更好地理解小胶质细胞介导的神经毒性所涉及的机制。通过利用体外和体内模型，提出的目标将系统地阐明内源性和外源性损伤之间的相互作用及其对小胶质细胞活化和神经变性的协同作用。此外，将检查参与这些过程的特定相互作用蛋白和途径，并将这些结果在PD患者的人体组织中进一步验证，并与其他神经退行性疾病进行比较。这些目标的完成将提供一个更好的理解在PHOX遗传和环境因素的相互作用。最后，识别参与小胶质细胞介导的神经退行性变的特定蛋白质和途径可能为PD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.