Autophagy in aging and neurodegeneration

衰老和神经退行性疾病中的自噬

• 批准号: 9791018
• 负责人: ANDREA STAVOE
• 金额: $ 8.08万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-30 至 2020-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9791018
• 关键词: Advisory Committees; Affect; Age; Aging; Alzheimer' s Disease; American; Animals; Autophagocytosis; Autophagosome; Award; Axon; Biogenesis; Biological Models; Caenorhabditis elegans; Cell Culture Techniques; Cell Differentiation process; Cells; Cellular Stress; Complex; Data; Defect; Development Plans; Disease Progression; Distal; Environment; Equipment; Faculty; Gene Transfer; Genetic; Genetic Screening; Goals; Growth; Homeostasis; Human; Huntington Disease; In Vitro; Kinetics; Lead; Learning; Life Expectancy; Link; Longevity; Lysosomes; Maintenance; Mammalian Cell; Mentors; Mentorship; MicroRNAs; Microscopy; Mitotic; Modeling; Molecular; Molecular Target; Mus; Nerve Degeneration; Nervous system structure; Neurodegenerative Disorders; Neuroglia; Neuronal Dysfunction; Neurons; Parkinson Disease; Pathology; Pathway interactions; Peer Review; Pennsylvania; Persons; Process; Productivity; Proteins; Regulation; Research; Resolution; Resources; Risk Factors; Role; Starvation; Time; Training; Training Support; Universities; Viral Genes; Work; Yeasts; adeno-associated viral vector; age related; age related neurodegeneration; aged; base; career development; experience; experimental study; healthspan; improved; in vivo; in vivo Model; in vivo imaging; member; molecular targeted therapies; neuron loss; novel; preservation; research and development; retrograde transport; risk sharing; trafficking

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.

随着人类预期寿命的增加，神经退行性疾病已经成为巨大的经济和社会负担。自噬的失调与神经退行性疾病有关，包括阿尔茨海默病、帕金森病和亨廷顿病。虽然许多研究已经描述了自噬及其在酵母和哺乳动物细胞培养中的细胞稳态中的作用，但对神经元中的自噬知之甚少，特别是在完整的活体动物中。在哺乳动物原代神经元中，自噬体生物发生随着年龄的增长而减少;在来自老年小鼠的原代神经元中，自噬体组装因子的动力学也被破坏（Stavoe等人，在同行审查下）。了解自噬的各个阶段如何随着年龄的增长而变化，以及自噬在衰老过程中如何调节，对于开发与年龄相关的神经退行性疾病的治疗方法将非常重要。此外，揭示衰老如何调节具有完整神经系统的活体动物的自噬，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改变以及自噬如何随年龄调节的鉴定将在神经元自噬和贩运世界专家Erika Holzbaur博士（导师，宾夕法尼亚大学）的指导下进行。PI将与超分辨率显微镜（Melike Lakadamyali博士和Andrea Stout，UPenn）和病毒基因转移（John Wolfe博士，UPenn）的世界专家合作，学习新的最先进的方法，以融入该项目。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PI的拟议研究和成长。PI将设在宾夕法尼亚大学，在整个指导奖期间由Erika Holzbaur博士指导。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的职业发展资源。拟议的研究和开发计划将使PI能够表征自噬途径的年龄相关变化，并确定自噬在初级哺乳动物神经元和C. elegans neurons in vivo.这一初步研究将使PI在小鼠和C. elegans模型的老化和神经变性，从而创造了一个利基PI作为一个独立的教员。这些研究将确定在衰老和神经退行性变的背景下改善神经系统健康的潜在分子靶点。拟议的研究是PI长期目标的一部分，即研究神经元衰老和神经退行性变的进化保守分子机制，特别关注神经元自噬，并将这些发现应用于改善神经退行性疾病。