Autophagy in aging and neurodegeneration

项目摘要/摘要 随着人类预期寿命的延长，神经退行性疾病已成为巨大的经济和社会负担 已经增加了。自噬的错误调节与神经退行性疾病有关，包括 阿尔茨海默氏症、帕金森氏症和亨廷顿氏症。虽然许多研究表明 酵母和哺乳动物细胞培养中的自噬及其在细胞内稳态中的作用，知之甚少 神经元中的自噬，特别是在完好无损的活动物的背景下。自噬小体生物发生减少 随着哺乳动物初级神经元的年龄增长，自噬小体组装因子的动力学也变得 在老年小鼠的初级神经元中被破坏(Stavoe等人，在同行审查下)。了解所有阶段如何 自噬随年龄的变化以及如何在衰老过程中调节自噬对发育将是重要的 治疗与年龄相关的神经退行性疾病。此外，揭示衰老是如何调节的 在具有完整神经系统的活体动物中，自噬将考虑到复杂、动态的自然 神经退行性疾病发展的环境。与年龄相关的改变在老年人中的识别 自噬途径以及自噬是如何随年龄而调节的，将在Dr。 Erika Holzbaur(宾夕法尼亚大学导师)，神经元自噬和贩运方面的世界专家。这个 派将与世界超分辨率显微镜专家(梅利克·拉卡达马利博士和安德里亚博士)合作 Stout，UPenn)和病毒基因转移(John Wolfe，UPenn)，以学习最先进的新方法 融入到项目中。 PI已经组建了一个优秀的研究咨询委员会，该委员会将提供培训、支持和 指导，以促进拟议的学习和成长的PI。PI的总部将设在加州大学 在整个导师奖期间，在Erika Holzbaur博士的指导下，宾夕法尼亚州。在……里面 此外，私家侦探还可以使用最先进的设施和设备，以及优秀的职业资源 宾夕法尼亚大学的发展。拟议的研究和发展计划将使 PI来表征与年龄相关的自噬途径的变化，并确定自噬的程度 在原生哺乳动物神经元和线虫神经元体内均有调节。这项初步研究将允许 然后在小鼠和线虫衰老和线虫模型中调节体内神经元自噬的PI 神经退化，从而为PI作为独立教员创造了一个利基市场。这些研究将 在以下背景下确定改善神经系统健康跨度的潜在分子目标 衰老和神经退化。拟议的研究是私家侦探长期目标的一部分，目的是调查 进化保守的神经元衰老和神经退行性变的分子机制，具有特殊的 专注于神经元自噬，并将这些发现应用于改善神经退行性疾病。

Project Summary/Abstract Neurodegenerative diseases have become enormous financial and societal burdens as human life expectancy has increased. Misregulation of autophagy has been implicated in neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease and Huntington's disease. While many studies have characterized autophagy and its role in cellular homeostasis in yeast and mammalian cell culture, much less in known about autophagy in neurons, especially in the context of intact, living animals. Autophagosome biogenesis decreases with age in mammalian primary neurons; the kinetics of autophagosome assembly factors also become disrupted in primary neurons from aged mice (Stavoe et al., under peer review). Understanding how all stages of autophagy change with age and how autophagy is regulated during aging will be important for developing treatments for age-related neurodegenerative diseases. Furthermore, uncovering how aging modulates autophagy in living animals, with intact nervous systems, will take into account the complex, dynamic natural environment in which neurodegenerative diseases develop. The identification of age-related alterations in the autophagy pathway and how autophagy is modulated with age will be conducted under the guidance of Dr. Erika Holzbaur (mentor, University of Pennsylvania), a world expert in neuronal autophagy and trafficking. The PI will collaborate with world experts in super-resolution microscopy (Drs. Melike Lakadamyali and Andrea Stout, UPenn) and viral gene transfer (Dr. John Wolfe, UPenn) to learn new state-of-the-art approaches to incorporate into the project. The PI has assembled an excellent research advisory committee who will provide the training, support, and mentoring to facilitate the proposed studies and growth of the PI. The PI will be based at the University of Pennsylvania, under the guidance of Dr. Erika Holzbaur during the entire period of the mentored award. In addition, the PI has access to state-of-the-art facilities and equipment, as well as excellent resources for career development at the University of Pennsylvania. The proposed research and development plan will enable the PI to characterize the age-related alterations to the autophagy pathway and determine how autophagy is regulated in both primary mammalian neurons and C. elegans neurons in vivo. This initial research will allow the PI to then modulate neuronal autophagy in vivo in both murine and C. elegans models of aging and neurodegeneration, thus creating a niche for the PI as an independent faculty member. These studies will determine potential molecular targets for improving the healthspan of the nervous system in the context of aging and neurodegeneration. The proposed studies are part of the PI's long-term goal to investigate the evolutionarily conserved molecular mechanisms of neuronal aging and neurodegeneration, with a particular focus on neuronal autophagy, and to apply these discoveries to ameliorating neurodegenerative diseases.