Functional characterization of the Alzheimer's disease Epigenome

阿尔茨海默病表观基因组的功能表征

• 批准号: 10429504
• 负责人: Michael Ryan Corces
• 金额: $ 8.94万
• 依托单位: J. DAVID GLADSTONE INSTITUTES
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-15 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10429504
• 关键词: 3-Dimensional; Alzheimer' s Disease; Biological Assay; Brain; Brain region; CRISPR interference; Chemicals; Chromatin; Clinical; Code; Complement; DNA; Disease; Environment; Epigenetic Process; Genetic; Heritability; Impaired cognition; Individual; Institutes; Lead; Modification; Molecular; Mutation; Nerve Degeneration; Neurodegenerative Disorders; Pathogenesis; Patients; Play; Prevention; Public Health; Regulatory Element; Research; Research Personnel; Risk; Role; Therapeutic Intervention; Time; United States; Untranslated RNA; Work; age related; cell type; cognitive function; epigenome; epigenomics; genome wide association study; healthy aging; lifetime risk; mortality; nervous system disorder; novel; prevent; programs; progressive neurodegeneration

Project Summary/Abstract Alzheimer’s disease (AD) manifests as a devastating age-related progressive neurodegeneration. This neurodegeneration and the concomitant loss of cognitive function plagues more than 44 million individuals worldwide. Our understanding of the molecular pathogenesis of AD remains incomplete and no therapies exist to prevent, stop, or cure the associated neurodegeneration. This marks one of the greatest unmet clinical needs of our time. Through decades of research, genome-wide association studies have identified heritable coding and non-coding mutations that lead to an increased risk of developing AD. Many of these mutations, however, remain largely under-characterized and their contribution to AD pathogenesis remains unclear. Moreover, it has become increasingly clear that an individual’s lifetime risk of developing AD is not merely governed by genetics. In addition, the epigenome, the complement of all of the chemical and physical modifications imposed on DNA that do not change the underlying sequence, is also thought to play a crucial role. This project aims to define the epigenetic (Aim 1) and genetic (Aim 2) components of AD through profiling of the open chromatin landscapes and three-dimensional chromatin interactions in brain regions and primary cell types of patients with and without AD. These characterizations will identify key AD-related regulatory elements that will be functionally validated with CRISPR interference tiling assays (Aim 3). Taken together, this project will provide an unprecedented picture of the AD epigenome, identifying novel aspects of AD pathogenesis and nominating putative avenues for therapeutic intervention. This work will be performed within the Gladstone Institute of Neurological Disease which is an ideal environment to perform such disease-relevant research, providing all of the facilities needed for the proposed research and a collaborative and enriching culture for an early stage investigator. Cumulatively, this work will launch my independent research program at the intersection of epigenomics and neurological disease.

项目总结/摘要 阿尔茨海默病（AD）表现为一种破坏性的与年龄相关的进行性神经变性。这 神经变性和随之而来的认知功能丧失困扰着超过4400万人 国际吧我们对AD的分子发病机制的理解仍然不完全，也没有治疗方法 来预防、阻止或治愈相关的神经退化。这标志着最大的未满足的临床需求之一 我们的时代。 通过几十年的研究，全基因组关联研究已经确定了可遗传编码和非编码 导致AD风险增加的突变。然而，这些突变中的许多在很大程度上仍然存在。 特征不足，其对AD发病机制的贡献仍不清楚。此外，它已成为 越来越清楚的是，一个人一生中患AD的风险不仅仅是由遗传决定的。在 此外，表观基因组，对DNA施加的所有化学和物理修饰的补充， 不改变潜在的序列，也被认为发挥了至关重要的作用。该项目旨在定义 通过分析开放染色质景观，研究AD的表观遗传（Aim 1）和遗传（Aim 2）成分 和三维染色质的相互作用，在大脑区域和原代细胞类型的患者， AD.这些特征将确定关键的AD相关的调控元件，这些元件将在功能上得到验证 CRISPR干扰平铺测定（Aim 3）。总的来说，这个项目将提供前所未有的 AD表观基因组的图片，确定AD发病机制的新方面，并提名公认的途径， 治疗干预 这项工作将在格莱斯顿神经疾病研究所进行，这是一个理想的环境 进行此类疾病相关研究，提供拟议研究所需的所有设施， 合作和丰富的文化为早期阶段的调查。累积起来，这项工作将启动我的 在表观基因组学和神经系统疾病的交叉点的独立研究计划。