Role of HDAC2 as a modulator of aging and Alzheimer's disease phenotypes in stem-cell derived neurons

标题：HDAC2在干细胞来源的衰老和阿尔茨海默病表型中的调节作用 神经元。 项目摘要/摘要 大脑老化是许多神经退行性疾病的重要因素，包括阿尔茨海默病(AD)， 并受到表观遗传机制的严格调控。直到最近，研究人类神经老化一直是 由于相对难以接触到活的脑组织，这是具有挑战性的。细胞重编程的最新进展， 要么通过从体细胞诱导干细胞并分化为神经系，要么通过直接 体细胞向神经元的转分化一直是变革性的。然而，全球对 人类阿尔茨海默病细胞模型缺乏表观遗传学变化和年龄的贡献。最新研究 研究表明，表观遗传调节剂组蛋白脱乙酰基酶2(HDAC2)在AD和老年人中异常升高 大脑。申请者杰西卡·E·杨博士建议结合她在干细胞方面的丰富经验 在衰老生物学、功能基因组学和神经学指导下的生物学和阿尔茨海默病模型 线粒体生物学测试HDAC2是人类神经元细胞年龄驱动因素这一重要假说 并与AD相关的表型有关。这个项目将提出三个关键问题：1)表观遗传学 调控因子HDAC2驱动与老化的人类神经元相关的表观基因组和转录改变？2)确实如此 HDAC2表达的调节改变了人神经元的细胞衰老表型？3)调节 人类神经元中HDAC2的表达影响与AD病理相关的细胞表型？要解决这个问题 问题，杨博士将继续进行功能基因组和细胞生物学实验，基于对 Hdac2在hipsc来源和转分化的人类神经元中的表达。这项工作将会取得进展 了解衰老与阿尔茨海默病发病机制的具体途径并评价HDAC2作为 一个开发与年龄相关的AD体外研究的工具。杨博士是麻省理工学院新任助理教授。 他是芝加哥大学干细胞和再生医学研究所的一名成员 华盛顿。她将把75%的时间投入到这个奖项下的研究中，并将用 老年生物学、神经病理学、表观基因组学和转录组分析方面的教学培训。这次培训将 由1)部门和大学课程，2)研讨会和期刊俱乐部3)负责任的行为组成 研究课程和4)国内和国际会议。杨医生将由彼得医生指导 拉比诺维奇博士、杰伊·申杜尔博士、C·德克·基恩博士和理查德·莫里森博士。 这些知名科学家是衰老生物学、功能基因组学、神经病理学、 和神经线粒体生物学。杨博士会见了她的每一位导师，讨论了这一问题 项目，并将在课程期间继续定期与他们会面(在导师信中指定) 这个奖项的获得者。预计她将以通讯或共同通讯作者的身份制作手稿，并 在这个奖项的过程中竞争R-Level奖助金。该项目将整合杨博士目前的 具有额外培训的专业知识，以开发全面的、独立的研究计划。

Title: Role of HDAC2 as a modulator of aging and Alzheimer’s disease phenotypes in stem-cell derived neurons. Project Summary/Abstract Brain aging is a significant contributor to many neurodegenerative disorders, including Alzheimer’s disease (AD), and is tightly regulated by epigenetic mechanisms. Until recently, studying human neural aging has been challenging due to the relative inaccessibility of living brain tissue. Recent advances in cellular reprogramming, either by inducing stem cells from somatic cells and differentiating to a neural lineage or by direct transdifferentiation of somatic cells to neurons, have been transformative. However, a global understanding of epigenetic changes and the contribution of age in a human cellular model of AD is lacking. Recent studies demonstrate that the epigenetic regulator histone deacetylase 2 (HDAC2) is abnormally elevated in AD and aged brains. The applicant, Dr. Jessica E. Young, is proposing to combine her considerable experience in stem cell biology and Alzheimer’s disease modeling with mentorship in aging biology, functional genomics, and neuronal mitochondrial biology to test the overarching hypothesis that HDAC2 is a driver of cellular age in human neurons and contributes to AD-relevant phenotypes. This project will ask three critical questions: 1) Does the epigenetic regulator HDAC2 drive epigenomic and transcriptomic changes related to aging human neurons? 2) Does modulation of HDAC2 expression alter cellular aging phenotypes in human neurons? 3) Does modulation of HDAC2 expression affect cellular phenotypes relevant to AD pathology in human neurons? To address this questions, Dr. Young will pursue functional genomic and cell biological experiments based on modulation of HDAC2 expression in hiPSC-derived and transdifferentiated human neurons. This work will advance understanding on specific pathways that link aging with AD pathogenesis and evaluate the utility of HDAC2 as a tool to develop age-relevant AD in vitro studies. Dr. Young is a new Assistant Professor in the Department of Pathology and a member of the Institute for Stem Cell and Regenerative Medicine at the University of Washington. She will devote 75% of her time to research under this award and will supplement her research with didactic training in aging biology, neuropathology, and epigenomic and transcriptomic analyses. This training will be comprised of 1) departmental and university courses, 2) seminars and journal clubs 3) responsible conduct of research courses and 4) national and international conferences. Dr. Young will be mentored by Dr. Peter Rabinovitch, Dr. Jay Shendure, Dr. C.Dirk Keene, and Dr. Richard Morrison at the University of Washington. These established scientists are renowned experts in biology of aging, functional genomics, neuropathology, and neuronal mitochondrial biology, respectively. Dr. Young has met with each of her mentors to discuss this project and will continue to meet with them at regular intervals (specified in mentorship letters) during the course of this award. She is expected to produce manuscripts as corresponding or co-corresponding author and be competitive for R-level grants during the course of this award. This project will integrate Dr. Young’s current expertise with additional training to develop a well-rounded, independent research program.