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

描述（由申请人提供）：该提案提供了一个指导性的研究和职业发展计划，用于建立一个独立的学术研究生涯，重点是阐明神经衰老和神经退行性变的基本机制。候选人目前是儿童医院和哈佛医学院分子生物学系和医学系的讲师。根据提议，候选人将在Frederick Alt博士、Li-Huei Tsai博士和布鲁斯扬克纳博士的指导和指导下进行研究，他们分别是小鼠遗传学、DNA修复、神经生物学和年龄相关神经退行性疾病方面的最重要专家。在该奖项的后半部分，候选人应该能够成功地寻求独立的研究项目资助（RO 1）支持，用于从他的指导研究中发展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（Sirt 6）是一种主要的神经组蛋白去乙酰化酶，对神经功能有影响。在拟议的研究计划中，候选人将研究Sirt 6在整个生命周期中维持神经元完整性和认知功能的作用（Aim 1），并通过使用新的突变小鼠品系和各种技术，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Sirt 6在阿尔茨海默病中的潜在作用（Aim 2）。 一个个性化的职业发展计划，充分利用了非常强大的指导团队和机构环境的专业知识和资源，建议候选人让他专注于他的奖学金神经衰老和神经退行性疾病，发展在神经病理学和基础神经生物学的专业知识老化和神经退行性疾病，并训练他使用先进的神经生物学和神经行为方法。该机构完全致力于提供必要的资源和培训，以帮助候选人建立自己的独立职业生涯。 越来越多的人患有与年龄有关的痴呆症，主要是阿尔茨海默病，是21世纪最大的公共卫生挑战之一，但没有治疗方法。拟议研究的集体结果将提供与正常大脑生理学，衰老和神经变性相关的过程的见解，并加深对sirtuin生物学的理解。最终，拟议的研究可能为确定阿尔茨海默病和其他年龄相关神经退行性疾病的新治疗靶点和预防方法提供基础。

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.