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作为衰老和阿尔茨海默氏病表型的角色 神经元。 项目摘要/摘要 大脑衰老是许多神经退行性疾病的重要因素，包括阿尔茨海默氏病（AD），， 并受到表观遗传机制的严格调节。直到最近，研究人类神经衰老一直是 由于活着的脑组织的相对无法访问，具有挑战性。细胞重编程的最新进展， 通过诱导的干细胞从体细胞并分化为神经元谱系或直接 体细胞向神经元的转分化已经转化。但是，全球理解 缺乏表观遗传变化和AD人类细胞模型中年龄的贡献。最近的研究 证明表观遗传调节剂Hisstone脱乙酰基酶2（HDAC2）在AD中绝对升高 大脑。杰西卡·E·杨（Jessica E. 生物学和阿尔茨海默氏病建模，具有衰老生物学，功能基因组学和神经元的心态 线粒体生物学测试了总体假设，即HDAC2是人类神经元细胞年龄的驱动力 并有助于与广告相关的表型。该项目将提出三个关键问题：1）表观遗传 调节剂HDAC2驱动与衰老人神经元有关的表观基因组和转录组变化？ 2）做 HDAC2表达的调节改变了人神经元中的细胞衰老表型？ 3）调制 HDAC2表达会影响与人类神经元中AD病理学相关的细胞表型？解决这个问题 问题，Young博士将基于调制 HIPSC衍生和转分化的人类神经元中的HDAC2表达。这项工作将进步 了解将衰老与AD发病机理联系起来的特定途径，并评估HDAC2的效用 一种开发与年龄相关的广告体外研究的工具。 Young博士是部门的新助理教授 病理学和大学干细胞和再生医学研究所成员 华盛顿。她将花75％的时间根据该奖项进行研究，并将她的研究补充 老化生物学，神经病理学以及表观基因组学和转录组分析的教学训练。这个培训将 完成1）系课程和大学课程，2）SEMIAR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。杨博士将由彼得博士考虑 Rabinovitch，Jay Shendure博士，C。DirkKeene博士和华盛顿大学的Richard Morrison博士。 这些成熟的科学家是衰老，功能基因组学，神经病理学，神经病理学生物学专家 和神经元线粒体生物学。 Young博士与她的每位导师会面，讨论这一点 项目，并将在课程期间定期与他们会面 这个奖项。预计她将产生手稿作为相应或相应的作者，并成为 在本奖项期间，R级赠款的竞争力。该项目将整合杨氏博士的当前 通过额外培训的专业知识，以制定全面的独立研究计划。