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

HDAC2 作为干细胞衍生神经元衰老和阿尔茨海默氏病表型调节剂的作用

• 批准号: 10377380
• 负责人: Jessica Elaine Young
• 金额: $ 12.05万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-15 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10377380
• 关键词: Address; Affect; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease model; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer' s disease risk; Amyloid beta-Protein; Award; Biological; Biology; Biology of Aging; Brain; Cell Aging; Cell Differentiation process; Cell model; Cells; Cognition; Embryo; Epigenetic Process; Fibroblasts; Genes; Genetic; Goals; Grant; HDAC2 gene; Health; Histone Deacetylase; Human; In Vitro; Individual; Institutes; International; Journals; Laboratories; Learning; Letters; Link; Manuscripts; Mediator of activation protein; Mentors; Mentorship; Mitochondria; Modeling; Neurodegenerative Disorders; Neurons; Pathogenesis; Pathogenicity; Pathology; Pathway interactions; Patients; Phenotype; Proteins; Regenerative Medicine; Rejuvenation; Repression; Research; Research Training; Risk; Role; Scientist; Somatic Cell; Source; Specific qualifier value; Study Subject; Technology; Testing; Thinness; Time; Tissue Model; Tissues; Training; Universities; Washington; Work; age related; age related neurodegeneration; aged; aging brain; base; brain tissue; cell type; cognitive function; design; disease phenotype; disease-in-a-dish; epigenomics; experience; experimental study; functional genomics; genome editing; high throughput screening; histone deacetylase 2; human model; human subject; in vitro Model; induced pluripotent stem cell; knock-down; member; mind control; mouse model; nerve stem cell; neuropathology; non-demented; novel; overexpression; professor; programs; relating to nervous system; responsible research conduct; stem cell biology; stem cell model; stem cells; symposium; tool; transcriptomics; transdifferentiation

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.

HDAC 2作为干细胞衍生的衰老和阿尔茨海默病表型调节剂的作用 神经元 项目总结/摘要 脑老化是许多神经退行性疾病的重要原因，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 由于活体脑组织的相对不可及性而具有挑战性。细胞重编程的最新进展， 或者通过从体细胞诱导干细胞并分化成神经谱系，或者通过直接 体细胞向神经元的转分化，已经是变革性的。然而，全球对 在AD的人类细胞模型中缺乏表观遗传变化和年龄的贡献。最近的研究 表明表观遗传调节剂组蛋白脱乙酰酶2（HDAC 2）在AD和老年人中异常升高， 大脑申请人Jessica E.她提议将联合收割机与她在干细胞方面的丰富经验 生物学和阿尔茨海默病建模与指导在衰老生物学，功能基因组学，神经元 线粒体生物学来测试HDAC 2是人类神经元细胞年龄的驱动因素的总体假设 并导致AD相关表型。该项目将提出三个关键问题：1）表观遗传是否 HDAC 2调节剂驱动与衰老人类神经元相关的表观基因组和转录组变化？2)并 HDAC 2表达的调节改变人类神经元的细胞衰老表型？3)是否调制 HDAC 2表达影响人类神经元中与AD病理学相关的细胞表型？为了解决这个 问题，杨博士将追求功能基因组和细胞生物学实验的基础上调制 HDAC 2在hiPSC衍生和转分化的人神经元中的表达。这项工作将推进 了解将衰老与AD发病机制联系起来的特定途径，并评估HDAC 2作为 开发年龄相关AD体外研究的工具。杨博士是一个新的助理教授在系 病理学和干细胞和再生医学研究所的成员， 华盛顿。她将把75%的时间用于该奖项下的研究，并将补充她的研究， 在衰老生物学、神经病理学、表观基因组学和转录组学分析方面的教学培训。本次培训将 包括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 研究课程和4）国家和国际会议。彼得博士将指导杨博士 华盛顿大学的拉宾诺维奇博士、杰伊·申杜雷博士、德克·基恩博士和理查德·莫里森博士。 这些著名的科学家是衰老生物学、功能基因组学、神经病理学、 和神经元线粒体生物学。杨博士与她的每一位导师都进行了讨论 项目，并将继续在课程期间定期与他们会面（在指导信中指定） 这个奖项。她预计将产生相应的或共同通信作者的手稿， 在这个奖项的过程中竞争R级赠款。该项目将整合杨博士目前的 专业知识与额外的培训，以制定一个全面的，独立的研究计划。