Autophagy in aging and neurodegeneration

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。自噬的错误调控与神经退行性疾病有关，包括阿尔茨海默病、帕金森氏病和亨廷顿病。虽然许多研究已经在酵母和哺乳动物细胞培养中表征了自噬及其在细胞内稳态中的作用，但对神经元的自噬知之甚少，特别是在完整的活动物的背景下。哺乳动物初级神经元中的自噬小体生物发生随着年龄的增长而减少；老年小鼠的初级神经元中的自噬小体组装因子的动力学也受到干扰(Stavoe等人，在同行审查下)。了解自噬的所有阶段如何随年龄变化，以及自噬在衰老过程中如何受到调节，对于开发与年龄相关的神经退行性疾病的治疗方法将是重要的。此外，揭示衰老如何调节神经系统完好的活动物的自噬，将考虑到神经退行性疾病发展的复杂、动态的自然环境。自噬途径中与年龄相关的变化以及自噬如何随年龄变化的识别将在世界神经元自噬和贩运专家Erika Holzbaur博士(Mentor，宾夕法尼亚大学)的指导下进行。PI将与超分辨率显微镜(宾夕法尼亚大学的Melike Lakadamali博士和Andrea Stout博士)和病毒基因转移(宾夕法尼亚大学的John Wolfe博士)方面的世界专家合作，学习纳入该项目的新的最先进的方法。国际和平研究所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，以促进国际和平研究所拟议的研究和成长。在整个导师奖期间，PI将驻在宾夕法尼亚大学，在Erika Holzbaur博士的指导下。此外，PI还可以使用最先进的设施和设备，以及宾夕法尼亚大学职业发展的优秀资源。拟议的研究和发展计划将使PI能够表征与年龄相关的自噬途径的变化，并确定自噬在体内的原始哺乳动物神经元和线虫神经元中是如何调节的。这项初步研究将允许PI在小鼠和线虫衰老和神经退化模型中调节体内神经元自噬，从而为PI作为独立教员创造一个利基。这些研究将确定在衰老和神经退化的背景下改善神经系统健康跨度的潜在分子靶点。这项拟议的研究是PI长期目标的一部分，目的是研究神经元衰老和神经退行性变的进化保守的分子机制，特别是神经元自噬，并将这些发现应用于改善神经退行性疾病。

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.