Elucidation of the role of Sirt6 in neural function, aging, and neurodegeneration

描述（由申请人提供）：本提案提供了一个指导的研究和职业发展计划，建立一个独立的学术研究生涯，专注于阐明神经衰老和神经变性的基本机制。该候选人目前是儿童医院和哈佛医学院分子生物学和医学系的讲师。根据提议，候选人将在Frederick Alt博士、Li-Huei Tsai博士和Bruce Yankner博士的指导下进行研究，他们分别是小鼠遗传学、DNA修复、神经生物学和与年龄相关的神经退行性疾病的顶尖专家。在奖项的后期，候选人应该能够成功地寻求独立研究项目资助（RO1），以支持从他的指导研究中发展出来的衰老和神经变性的神经生物学研究。候选人的初步工作表明Sirtuin 6 （Sirt6）是一种主要的神经组蛋白去乙酰化酶，与神经功能有关。在拟议的研究计划中，候选人将研究Sirt6在整个生命周期中维持神经元完整性和认知功能中的作用（目标1），并通过使用新的突变小鼠系和各种技术，包括组织病理学，电生理学，行为分析和分子生物学方法，阐明Sirt6在阿尔茨海默病中的潜在作用（目标2）。为候选人提供个性化的职业发展规划，充分利用特别强大的指导团队和机构环境的专业知识和资源，使其能够专注于神经衰老和神经退行性疾病的研究，培养其在衰老和神经退行性疾病的神经病理学和基础神经生物学方面的专业知识，并训练其使用先进的神经生物学和神经行为学方法。该机构完全致力于提供必要的资源和培训，帮助候选人建立自己的独立职业生涯。越来越多的人受到与年龄有关的痴呆症（主要表现为阿尔茨海默病）的影响，这是21世纪最大的公共卫生挑战之一，但目前尚无治疗方法。拟议研究的集体结果将为正常脑生理学，衰老和神经退行性变相关过程提供见解，并加深对sirtuin生物学的理解。最终，提出的研究可能为阿尔茨海默病和其他与年龄相关的神经退行性疾病的新治疗靶点和预防方法的确定提供基础。

DESCRIPTION (provided by applicant): This proposal provides a mentored research and career development program for the establishment of an independent academic research career focused on the elucidation of basic mechanisms of neural aging and neurodegeneration. The candidate is currently an Instructor in the Division of Molecular Biology and Department of Medicine at Children's Hospital and Harvard Medical School. As proposed, the candidate will conduct research under the mentorship and guidance of Dr. Frederick Alt, Dr. Li-Huei Tsai, and Dr. Bruce Yankner, who are foremost experts in mouse genetics, DNA repair, neurobiology, and age-related neurodegenerative disorders, respectively. During the latter portion of the award, the candidate should be well positioned to successfully seek independent research project grant (RO1) support for studies in the neurobiology of aging and neurodegeneration that develop from his mentored research. The candidate's preliminary work has shown that Sirtuin 6 (Sirt6) is a major neural histone deacetylase with implications for neural functioning. In the proposed research plan, the candidate will investigate the role of Sirt6 in maintenance of neuronal integrit and cognitive function across the lifespan (Aim 1), and elucidate a potential role of Sirt6 in Alzheimer's disease (Aim 2) by using novel mutant mouse lines, and a variety of techniques including histopathology, electrophysiology, behavioral analysis, and molecular biology approaches. A personalized career development plan that takes full advantage of the expertise and resources of the exceptionally strong mentoring team and institutional environment is proposed for the candidate to allow him to focus his scholarship on neural aging and neurodegeneration, to develop expertise in the neuropathology and basic neurobiology of aging and neurodegenerative disorders, and to train him in the use of advanced neurobiological and neurobehavioral methods. The institution is fully committed to providing the necessary resources and training to help the candidate establish his independent career. The increasing number of people affected by age-related dementia, mainly in the form of Alzheimer's disease, is one of the greatest public health challenges of the 21st century but no treatments are available. The collective results from the proposed research will provide insights into processes related to normal brain physiology, aging and neurodegeneration, as well as deepen the understanding of sirtuin biology. Ultimately, the proposed studies may provide a foundation for the identification of new therapeutic targets and preventive approaches for Alzheimer's disease and other age-related neurodegenerative disorders.