Novel Mechanisms of Adult Neurogenesis in Physiological and Pathological Contexts

描述（由申请人提供）：这是NIA独立科学家奖（K 02）的申请。候选人谢珍妮（Jenny Hsieh）博士是一个助理教授在她的第六年的分子生物学系在UT西南医学中心在达拉斯。在她的职业生涯中，谢博士已经建立了一个强大的出版记录（共23篇; 14篇来自她的独立实验室，来自联邦（NIA）和非联邦（Ellison Medical Foundation，Welch Foundation，CURE，ARPATP，CPRIT）来源的奖项和资金，以及指导。自2005年加入UT西南学院以来，Hsieh博士开发了一个独特的研究计划，重点是了解生理和病理背景下成人神经干细胞的表观遗传机制。然而，行政与教学工作的增加，却阻碍了谢博士的研究进度，使她只能投入一半的时间在研究上。K 02奖的获得将消除或限制这些义务，从而使Hsieh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）培养新开发的关于新颗粒神经元在癫痫发生中的作用的合作;（3）学习前沿技术的原理和实践（生化纯化，ChIP-seq和RNA-seq）从校园同事;（4）探索她新产生的REST条件性敲除小鼠，以更好地理解在生理和病理背景下（例如癫痫发作活动后）对神经元细胞命运重要的转录和表观遗传回路;（5）产生足够的 一系列资助申请的数据，以及准备这些申请的时间：她现有的R 01的竞争性更新申请，新的NIA R 01申请，以及额外的小额或探索性资助申请，也是NIA;（6）花更多的时间指导和与两名研究生，两名博士后研究员，两名研究助理和一名本科生在她的实验室互动;（7）邀请干细胞领域内外的合作者参与癫痫发作诱发海马神经可塑性的研究。该K 02奖项提供的稳定性和保护时间最终将支持三个新项目，探索脑损伤信号（如癫痫发作），成人神经干细胞和海马小生境之间的复杂关系，这些常驻干细胞在海马小生境中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，可以提高我们对癫痫发作活动影响大脑可塑性的复杂机制的理解，因此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程序的发育机制，这些机制有可能进一步治疗越来越多的与神经元损失或异常神经元功能相关的神经精神疾病，这可能对衰老期间维持认知功能特别重要。

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.