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Functional characterization of the Alzheimer's disease Epigenome

阿尔茨海默病表观基因组的功能表征

基本信息

批准号：
10414137
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
项目类别：
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/10414137
关键词：
3-Dimensional ATAC-seq Affect Age Alzheimer&apos 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&apos 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

项目摘要

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.

项目摘要/摘要阿尔茨海默病(AD)表现为一种与年龄相关的破坏性进行性神经变性。这神经变性和随之而来的认知功能丧失困扰着4400多万人全世界。我们对阿尔茨海默病分子发病机制的了解仍然不完全，也没有治疗方法预防、阻止或治愈相关的神经变性。这标志着最大的未得到满足的临床需求之一属于我们这个时代。经过几十年的研究，全基因组关联研究已经确定了可遗传的编码和导致AD风险增加的非编码突变。然而，这些突变中的许多仍然存在它们在AD发病机制中的作用尚不清楚。此外，它已经成为越来越清楚的是，一个人患阿尔茨海默病的终生风险不仅仅是由基因决定的。在……里面此外，表观基因组是对DNA施加的所有化学和物理修饰的补充，不要改变底层的顺序，也被认为起到了至关重要的作用。该项目旨在定义阿尔茨海默病的表观遗传成分(目标1)和遗传成分(目标2)通过描绘开放的染色质景观和三维染色质相互作用在脑区域和原代细胞类型的有无和无广告。这些特征将确定将在功能上进行验证的与AD相关的关键监管要素采用CRISPR干扰平铺试验(AIM 3)。总而言之，这个项目将提供一个前所未有的 AD表观基因组图，确定AD发病机制的新方面，并提名可能的治疗途径治疗性干预。这项工作将在应用程序专家Howard Chang博士的共同指导下进行表观基因组学与疾病的关系，以及斯坦福大学脑老化和阿尔茨海默病研究的领导者托马斯·蒙廷博士医学院，一所世界级的研究机构。目标1和目标2将主要在 K99指导阶段，而目标3和4将主要在R00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方面进行严格的培训计划。神经退化，使我能够在新的方向上扩展我的研究，学习新的技术，并获得建立一个专注于AD表观遗传学的独立实验室的知识和技能。