Mitochondrial Dynamics in Neurodegeneration

描述（由申请人提供）：该提案提供了一个指导的职业发展计划和研究计划，旨在促进首席研究员发展成为一个完全独立的临床研究人员，目标是在理解线粒体参与帕金森病（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，特别是帕金森病有关。此外，这些都是老化神经元的疾病，线粒体损伤可能导致老化神经元容易受到额外的损伤。然而，许多与年龄相关的神经元线粒体功能和维持的变化仍然没有得到很好的理解。线粒体是动态的细胞器，经历频繁的分裂（裂变）、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、潜在治疗方法和晚期并发症具有重要意义。此外，线粒体分裂和融合在细胞死亡机制和线粒体DNA损伤保护中起着核心作用，线粒体融合基因的特定缺陷导致神经退行性疾病。在帕金森病中，选择性易损神经元都含有细长的轴突，这更依赖于适当的线粒体维护和动力学。然而，这些线粒体过程很难直接研究，而且关于年龄相关的变化或多巴胺能神经元或慢性PD模型的变化尚不清楚。使用一种新的方法来直接测量活神经元中单个线粒体的融合和裂变以及其他调查方法，拟议的研究将1)评估神经元线粒体动力学中与年龄相关的变化；2)确定线粒体动力学是否在慢性帕金森模型中发生改变，重要的是，调节这些过程是否具有神经保护作用；3)评估parkin对线粒体动力学及其调节因子的影响，因为parkin与已知的线粒体动力学调节因子相似。这些研究可能为帕金森病新的线粒体治疗靶点奠定基础。除了拟议的研究之外，还将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，相关培训和独特适合机构环境的方面，制定详细的定制职业发展计划。

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.