Mitochondrial Dynamics in Neurodegeneration

描述(由申请者提供)：本建议提供了一个有指导的职业发展计划和研究建议，旨在促进首席研究员发展成为完全独立的临床医生和研究人员，目标是在理解线粒体参与帕金森氏病(PD)和其他神经退行性疾病方面做出重大贡献。线粒体功能障碍越来越多地与神经退行性疾病有关，尤其是在帕金森病中。此外，这些都是老化神经元的疾病，线粒体损伤可能会导致老化神经元对额外刺激的脆弱性。然而，许多与年龄相关的神经元线粒体功能和维护的变化仍然没有被很好地了解。线粒体是动态细胞器，经历频繁的分裂、融合和运输。这些动态过程对突触的形成和功能至关重要，这对帕金森病的发病机制、潜在的治疗方法和晚期并发症具有重要意义。此外，线粒体的分裂和融合在细胞死亡机制和对线粒体DNA损伤的保护中起着核心作用，线粒体融合基因的特定缺陷会导致神经退行性疾病。在帕金森病中，选择性脆弱的神经元都含有细长的轴突，这些轴突更依赖于适当的线粒体维持和动力学。然而，这些线粒体过程一直很难直接研究，而且对年龄相关的变化、多巴胺能神经元或帕金森病的慢性模型也知之甚少。使用一种新的方法直接测量活神经元中单个线粒体的融合和裂变，以及其他研究方法，拟议的研究将1)评估神经元线粒体动力学的年龄相关变化；2)确定线粒体动力学在慢性PD模型中是否发生改变，以及重要的是，调节这些过程是否可以起到神经保护作用；3)评估parkin对线粒体动力学及其调节的影响，因为parkin与已知的线粒体动力学调节因子有相似之处。这些研究可能为治疗帕金森病的新的线粒体治疗靶点奠定基础。除了拟议的研究外，还在神经退行性疾病专家的指导下，利用经验丰富的资深科学家的专业知识、相关知识、培训和机构环境中独特适合的方面，详细制定了定制的职业发展计划。

DESCRIPTION (provided by applicant): This proposal provides a mentored career development plan and research proposal designed to facilitate the principal investigator's development into a fully independent clinician-researcher, with the goal of making significant contributions in understanding mitochondrial involvement in Parkinson's disease (PD) and other neurodegenerative diseases. Mitochondrial dysfunction is increasingly implicated in neurodegenerative diseases, particularly in PD. In addition, these are diseases of aging neurons, and mitochondrial impairment may contribute to the vulnerability of aging neurons to additional insult. However, many age-related changes in neuronal mitochondrial function and maintenance are-still not well understood. Mitochondria are dynamic organelles, undergoing frequent division (fission), fusion, and transport. These dynamic processes are critical for synapse formation and function, which has implications for pathogenesis, potential therapeutics, and late complications in PD. In addition, mitochondrial fission and fusion are centrally involved in cell death mechanisms and protection against mitochondrial DNA damage, and specific defects in mitochondrial fusion genes cause neurodegenerative diseases. In PD, the selectively vulnerable neurons all contain long and thin axons, which are more dependent on proper mitochondrial maintenance and dynamics. Yet these mitochondrial processes have been difficult to study directly, and much is not known about age-related changes or in dopaminergic neurons or chronic models of PD. Using a novel method developed to directly measure fusion and fission in individual mitochondria in live neurons and additional investigative methods, the proposed studies will 1) evaluate age-related changes in neuronal mitochondrial dynamics; 2) determine whether mitochondrial dynamics are altered in a chronic model of PD, and, importantly, whether regulating these processes can be neuroprotective; and 3) evaluate the influence of parkin on mitochondrial dynamics and its regulators, since parkin has similarities to known regulators of mitochondrial dynamics. These studies could potentially lay the groundwork for new mitochondrial therapeutic targets in PD. In addition to the proposed research, a customized career development plan is detailed, under the mentorship of an expert in neurodegenerative diseases, and utilizing the expertise of experienced senior scientists, relevant, training, and the uniquely suited aspects of the institutional environment.