Autophagy in aging and neurodegeneration

衰老和神经退行性疾病中的自噬

• 批准号: 10401942
• 负责人: ANDREA STAVOE
• 金额: $ 24.9万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 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 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10401942
• 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

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.

项目总结/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。 增加了。自噬的失调与神经退行性疾病有关，包括 阿尔茨海默氏病、帕金森氏病和亨廷顿氏病。虽然许多研究都描述了 自噬及其在酵母和哺乳动物细胞培养中的细胞内稳态中的作用， 神经元的自噬，尤其是在完整的活体动物中。自噬体生物合成减少 随着年龄的增长，在哺乳动物的初级神经元;自噬体组装因子的动力学也成为 在来自老年小鼠的原代神经元中被破坏（Stavoe等人，在同行审查下）。了解所有阶段 随着年龄的增长，自噬的变化以及自噬在衰老过程中的调节方式将对开发 治疗与年龄相关的神经退行性疾病。此外，揭示衰老如何调节 在活的动物中，具有完整的神经系统的自噬，将考虑到复杂的，动态的自然 神经退行性疾病发展的环境。年龄相关改变的鉴定 自噬途径以及自噬如何随着年龄的增长而调节将在Dr. Erika Holzbaur（导师，宾夕法尼亚大学），神经元自噬和贩运的世界专家。的 PI将与世界各地的超分辨率显微镜专家（Melike Lakadamyali博士和Andrea博士）合作 Stout，UPenn）和病毒基因转移（Dr. John Wolfe，UPenn）来学习新的最先进的方法， 纳入项目。 PI已经组建了一个优秀的研究咨询委员会，他们将提供培训，支持， 指导以促进PI的拟议研究和成长。PI将设在大学， 宾夕法尼亚州，在埃里卡Holzbaur博士的指导下，在整个指导奖期间。在 此外，PI还可以使用最先进的设施和设备，以及良好的职业资源 宾夕法尼亚大学的发展。拟议的研究和发展计划将使 PI来表征自噬途径的年龄相关改变，并确定自噬是如何 在初级哺乳动物神经元和C. elegans neurons in vivo.这项初步研究将使 PI然后在鼠和C. elegans衰老模型， 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 确定潜在的分子靶点，以改善神经系统的健康状况， 老化和神经退化。拟议的研究是PI长期目标的一部分， 神经元老化和神经退行性变的进化保守分子机制， 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。