Novel Mechanisms of Adult Neurogenesis in Physiological and Pathological Contexts

生理和病理背景下成人神经发生的新机制

• 批准号: 8281205
• 负责人: Jenny Hsieh
• 金额: $ 12.92万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8281205
• 关键词: Ablation; Activities of Daily Living; Adult; Affect; Aging; Applications Grants; Area; Award; Behavioral; Binding; Biochemical; Brain; Brain Injuries; Cell Culture Techniques; Cells; ChIP-seq; Chromatin; Clinical; Code; Collaborations; Complex; Cytoplasmic Granules; Data; Development; Disease; Doctor of Philosophy; Educational process of instructing; Elements; Embryo; Enzymes; Epigenetic Process; Epilepsy; Epileptogenesis; Faculty; Foundations; Functional RNA; Funding; Gene Expression Profile; Gene Expression Regulation; Gene Targeting; Generations; Genes; Genetic Models; Genetic Transcription; Genome; Goals; Hippocampus (Brain); Histones; Homeostasis; Human; Independent Scientist Award; Individual; Knock-out; Knockout Mice; Laboratories; Lead; Learning; Light; Link; Lysine; Medical; Medical center; Memory; Mentors; Molecular; Molecular Biology; Mus; Natural regeneration; Nature; Nerve Regeneration; Nerve Tissue; Nervous System Trauma; Neuronal Plasticity; Neurons; Newborn Infant; Patients; Pharmaceutical Preparations; Physiological; Play; Postdoctoral Fellow; Process; Production; Proliferating; Public Health; Publications; RNA; Recruitment Activity; Regulation; Research; Research Personnel; Research Proposals; Rodent; Role; Seizures; Series; Signal Transduction; Site; Source; Specific qualifier value; Staging; Status Epilepticus; Stem cells; Structure of germinal center of lymph node; Techniques; Testing; Therapeutic; Time; Tissues; Translating; United States; Work; adult neurogenesis; base; career; cognitive function; exhaustion; genome wide association study; genome-wide; graduate student; granule cell; improved; interest; migration; mouse model; nerve stem cell; neurodevelopment; neurogenesis; neuron loss; neuropsychiatry; newborn neuron; novel; premature; professor; programs; promoter; protein complex; repaired; self-renewal; stem; stem cell biology; stem cell population; transcription factor; undergraduate student

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.

描述（由申请人提供）：这是NIA独立科学家奖（K02）的申请。候选人Jenny Hsieh博士是达拉斯德州大学西南医学中心分子生物学专业的助理教授，今年是她的第六年。在她的职业生涯中，Hsieh博士已经建立了良好的出版物记录(总共23篇，其中14篇来自她的独立实验室，联邦（NIA），非联邦（Ellison Medical Foundation, Welch Foundation， CURE， ARPATP， CPRIT）来源的奖励和资助，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项目，重点研究成体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%的时间用于研究。获得K02奖将消除或限制这些义务，从而允许Dr. Hsieh(1)推进她在成体神经干细胞自我更新和分化的基本机制方面的工作；(2)培育关于新颗粒神经元在癫痫发生中的作用的新合作；(3)向校园同事学习前沿技术（生化纯化、ChIP-seq、RNA-seq）的原理和实践；(4)探索她新生成的REST条件敲除小鼠，以更好地了解在生理和病理背景下对神经元细胞命运重要的转录和表观遗传回路，如癫痫发作活动后；(5)生成充足