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: 10251365
• 负责人: Michael Ryan Corces
• 金额: $ 24.9万
• 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/10251365
• 关键词: 3-Dimensional; ATAC-seq; Affect; Age; Alzheimer' s Disease; Architecture; Award; Biological Assay; Brain; Brain Diseases; Brain region; CRISPR interference; Chemicals; Chromatin; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; Code; Communities; Complement; DNA; Data; Data Set; Disease; Elements; Enhancers; Epigenetic Process; Evaluation; Foundations; Freezing; Funding; Genes; Genetic; Genetic Polymorphism; Genotype; Growth; Heart Diseases; Heritability; Human; Impaired cognition; Incidence; Individual; Institution; Intervention; Investigation; Knowledge; Laboratories; Late Onset Alzheimer Disease; Lead; Learning; Link; Maps; Mentors; Mentorship; Methods; Mind; Modification; Molecular; Mutation; Nerve Degeneration; Neurobiology; Neurodegenerative Disorders; Nucleic Acid Regulatory Sequences; Pathogenesis; Pathologic; Patients; Phase; Play; Prevention; Public Health; Regulator Genes; Regulatory Element; Research; Risk; Role; Single Nucleotide Polymorphism; Techniques; Testing; Therapeutic; Therapeutic Intervention; Time; Tissues; Training; Translating; United States; Universities; Untranslated RNA; Validation; Work; age related; age related neurodegeneration; aging brain; autosomal dominant Alzheimer' s disease; base; brain cell; cell type; cognitive function; comorbidity; data visualization; disease-causing mutation; epigenome; epigenomics; gene discovery; genome wide association study; healthy aging; insight; lifetime risk; medical schools; mortality; novel; online resource; patient subsets; presenilin-1; presenilin-2; prevent; progressive neurodegeneration; promoter; resilience; risk variant; skills; targeted treatment; web portal

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 under the co-mentorship of Dr. Howard Chang, an expert in the application of epigenomics to disease, and Dr. Thomas Montine, a leader in brain aging and AD, at the Stanford University School of Medicine, a world-class research institution. Aims 1 and 2 will be performed predominantly during the K99 mentored phase while Aims 3 and 4 will be performed predominantly during the R00 independent phase. If funded, this award will allow me to pursue a rigorous training plan in neurobiology and age-related neurodegeneration, enabling me to expand my research in new directions, learn new techniques, and acquire the knowledge and skills to establish an independent laboratory focused on the epigenetics of AD.

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遗传编码， 非编码突变导致AD风险增加。然而，许多这些突变仍然存在， 在很大程度上特征不足，它们对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，表观基因组是对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 这项工作将在应用专家霍华德·张博士的共同指导下进行 以及斯坦福大学的托马斯·蒙廷博士，他是大脑衰老和AD领域的领导者 医学院，世界一流的研究机构。目标1和2将主要在2010年期间执行。 K99指导阶段，而目标3和4将主要在R 00独立阶段执行。如果 这个奖项将使我能够在神经生物学和年龄相关的严格培训计划 神经变性，使我能够在新的方向上扩展我的研究，学习新的技术，并获得 知识和技能，建立一个独立的实验室，专注于AD的表观遗传学。