Novel Mechanisms of Adult Neurogenesis in Physiological and Pathological Contexts

描述(由申请者提供)：这是NIA独立科学家奖(K02)的申请书。这位候选人谢珍妮博士是达拉斯德克萨斯大学西南医学中心分子生物学系六年级的助理教授。在她的整个职业生涯中，谢博士已经建立了良好的发表记录(总共23篇；14篇来自她的独立实验室，奖项和资金来自联邦(NIA)、非联邦(埃利森医学基金会、韦尔奇基金会、CURE、ARPATP、CPRIT)来源和指导)。自2005年加入德克萨斯大学西南分校以来，谢博士制定了一项独特的研究计划，专注于了解成人神经干细胞在生理和病理背景下的表观遗传机制。然而，越来越多的行政和教学责任阻碍了谢博士的研究进展，以至于她只能将50%的时间投入到研究中。K02奖的获得将取消或限制这些义务，从而允许谢博士(1)推进她在成人神经干细胞自我更新和分化的基本机制方面的工作；(2)培养新发展的关于新颗粒神经元在癫痫发生中的作用的合作；(3)从校园同事那里学习尖端技术(生化提纯、芯片序列和RNA序列)的原理和实践；(4)探索她新产生的REST条件性基因敲除小鼠，以更好地了解在生理和病理背景下，如癫痫发作后，对神经细胞命运至关重要的转录和表观遗传回路；(5)产生足够的 这些活动包括：(1)为一系列的资助申请提供资料和准备时间；(2)为她现有的R01、一项新的NIA R01申请，以及一项额外的小额或试探性拨款申请，以及向NIA提出的额外小额资助申请提出竞争性续期申请；(6)在她的实验室花更多时间指导两名研究生、两名博士后研究员、两名助理研究人员和一名本科生；(7)邀请干细胞领域内外的合作者参与由癫痫发作活动诱导的海马神经可塑性研究。K02奖提供的稳定性和保护时间最终将支持三个新项目，这些项目探索癫痫发作、成人神经干细胞和海马区之间的复杂关系，这些常驻干细胞在海马区增殖并分化为新的颗粒神经元。因此，这些研究具有很大的潜力来提高我们对癫痫活动影响大脑可塑性的复杂机制的理解，从而可能为癫痫的治疗开辟新的途径。这些研究还可能揭示控制神经元谱系计划的发育机制，这些机制有可能进一步治疗越来越多的与神经元丢失或神经元功能异常有关的神经精神障碍，这可能对在衰老期间维持认知功能特别重要。 公共卫生相关性：神经系统的疾病、退化或创伤性损伤是美国最大的公共卫生问题之一，通常被认为是无法修复的，往往会对个人的功能能力造成灾难性的损害。然而，现在，对位于大脑特定生发中心和细胞培养中的神经干细胞的表征增加了神经组织功能再生的希望 可能是可行的，如果我们学会利用成人的神经发生来临床受益。这项研究提案将提高对神经干细胞生物学的理解，可能会导致神经系统修复和再生新药的开发。

DESCRIPTION (provided by applicant): This is an application for a NIA Independent Scientist Award (K02). The candidate, Jenny Hsieh, Ph.D. is an Assistant Professor in her sixth year on the Molecular Biology faculty at UT Southwestern Medical Center in Dallas. Throughout her career, Dr. Hsieh has established a strong record of publications (23 total; 14 from her independent laboratory, awards and funding from both federal (NIA), non-federal (Ellison Medical Foundation, Welch Foundation, CURE, ARPATP, CPRIT) sources, and mentoring. Since joining the UT Southwestern faculty in 2005, Dr. Hsieh has developed a unique research program with a focus on understanding the epigenetic mechanisms of adult neural stem cells in physiological and pathological contexts. However, increasing administrative and teaching obligations have hampered Dr. Hsieh's research progress, such that she is able to only devote 50% of her time on research. The receipt of a K02 award would remove or restrict these obligations, thus allowing Dr. Hsieh (1) to advance her work on basic mechanisms of adult neural stem cell self-renewal and differentiation; (2) to nurture a newly-developed collaboration on the role of new granule neurons in epileptogenesis; (3) to learn the principals and practice of cutting-edge techniques (biochemical purification, ChIP-seq and RNA-seq) from on campus colleagues; (4) to explore her newly-generated REST conditional knockout mice to better understand the transcriptional and epigenetic circuitry important for neuronal cell fate, in both physiological and pathological contexts, such as after seizure activity; (5) to generate sufficient data for a series of grant applications, and the time to prepare them: a competitive renewal application for her existing R01, a new NIA R01 application, and an additional small or exploratory grant application, also to NIA; (6) to spend more time mentoring and interacting with two graduate students, two postdoctoral fellows, two research associates, and one undergraduate student in her laboratory; and (7) to engage colaborators from both inside and outside the stem cel field in research on hippocampal neuroplasticity induced by seizure activity. The stability and protected time offered by this K02 award would ultimately support three new projects exploring the complex relationship between brain injury signals such as seizures, adult neural stem cells, and the hippocampal niche in which these resident stem cells proliferate and differentiate into new granule neurons. As such, these studies hold great potential to improve our understanding of the complex mechanisms by which seizure activity affect brain plasticity, and therefore may open new avenues for the treatment of epilepsy. These studies may also shed light on the developmental mechanisms controlling the neuronal lineage program which have the potential to further therapeutic approaches to an increasing number of neuropsychiatric disorders linked to neuronal loss or aberrant neuronal function, which may be of particular importance for maintaining cognitive function during aging. PUBLIC HEALTH RELEVANCE: Disease, degeneration or traumatic injury of the nervous system are among the greatest public health concerns in the United States and are generally considered irreparable, often causing catastrophic damage to the functional capacity of the individual. Now, however, characterization of neural stem cells residing within specific germinal centers of the brain and in cell culture raises hope that functional regeneration of nervous tissue may be feasible, if we learn to exploit adult neurogenesis for clinical benefit. The research proposal will lead to improved understanding of neural stem cell biology, possibly leading to the development of new drugs for repair and regeneration of the nervous system.