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.

标题：HDAC2 在干细胞衍生中作为衰老和阿尔茨海默病表型调节剂的作用 神经元。 项目概要/摘要 大脑老化是许多神经退行性疾病的一个重要原因，包括阿尔茨海默病（AD）、 并且受到表观遗传机制的严格调控，直到最近，人们一直在研究人类神经衰老。 由于活体脑组织相对难以接近，细胞重编程的最新进展具有挑战性， 通过从体细胞诱导干细胞并分化为神经谱系或直接 然而，体细胞向神经元的转分化已经发生了变革。 最近的研究缺乏表观遗传变化和年龄在 AD 人类细胞模型中的作用。 证明表观遗传调节剂组蛋白脱乙酰酶 2 (HDAC2) 在 AD 和老年人中异常升高 申请人 Jessica E. Young 博士提议结合她在干细胞方面的丰富经验。 生物学和阿尔茨海默病建模，并在衰老生物学、功能基因组学和神经元方面提供指导 线粒体生物学测试 HDAC2 是人类神经元细胞年龄驱动因素的总体假设 并有助于 AD 相关表型 该项目将提出三个关键问题：1）表观遗传学是否有效？ 调节因子 HDAC2 驱动与人类神经元衰老相关的表观基因组和转录组变化 2) 是吗？ HDAC2 表达的调节会改变人类神经元的细胞衰老表型 3) HDAC2 表达影响与人类神经元 AD 病理相关的细胞表型？ 问题，杨博士将从事基于调节的功能基因组和细胞生物学实验 HDAC2 在 hiPSC 衍生和转分化的人类神经元中的表达将取得进展。 了解将衰老与 AD 发病机制联系起来的特定途径，并评估 HDAC2 的效用 杨博士是该系的新助理教授。 病理学和干细胞与再生医学研究所成员 华盛顿，她将投入 75% 的时间用于该奖项的研究，并将用她的研究来补充。 衰老生物学、神经病理学以及表观基因组和转录组分析方面的教学培训。 包括 1) 院系和大学课程，2) 研讨会和期刊俱乐部 3) 负责任的行为 研究课程和 4) 国内和国际会议。杨博士将由彼得博士指导。 华盛顿大学的 Rabinovitch、Jay Shendure 博士、C. Dirk Keene 博士和 Richard Morrison 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、 杨博士分别与她的每位导师会面讨论了这一问题。 项目并将在课程期间继续定期与他们会面（在指导信中指定） 她预计将作为通讯作者或共同通讯作者撰写手稿并成为该奖项的获得者。 在该奖项期间，该项目将整合杨博士目前的研究成果，以竞争 R 级资助。 专业知识和额外培训，以开发全面的、独立的研究计划。