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 /摘要阿尔茨海默氏病（AD）表现为与年龄相关的渐进性神经变性。这神经变性和认知功能的伴随丧失困扰着超过4400万个人全世界。我们对AD分子发病机理的理解仍然不完整，没有疗法防止，停止或治愈相关的神经变性。这标志着最大的未满足临床需求之一我们的时间。通过数十年的研究，全基因组协会的研究已经确定了可遗传的编码和非编码突变会导致发展AD的风险增加。但是，其中许多突变仍然存在尚不清楚尚不清楚特征不足的特征及其对AD发病机理的贡献尚不清楚。而且，它已经成为越来越清楚的是，个人的终生发展风险不仅受遗传学的控制。此外，表观基因组，在DNA上施加的所有化学和物理修饰的完成不要改变基础序列，也被认为起着至关重要的作用。该项目旨在定义通过开放染色质景观的分析，表观遗传学（AIM 1）和AD的遗传（AIM 2）成分和有和没有的患者的主要细胞类型的三维染色质相互作用广告。这些字符将确定与广告相关的密钥调节元素，这些元素将在功能上验证带有CRISPR干扰分析测定法（AIM 3）。综上所述，该项目将提供空前的 AD表观基因组的图片，识别AD发病机理的新方面和提名的推定途径治疗干预。这项工作将在申请专家霍华德·张博士的委托下进行斯坦福大学大脑衰老和广告领域的领导者托马斯·蒙丁（Thomas Montine）博士的表观基因组学医学院，世界一流的研究机构。目标1和2将主要执行 K99修补阶段，而目标3和4将主要在R00独立阶段进行。如果该奖项资助，该奖项将使我能够制定一项严格的神经生物学和与年龄有关的培训计划神经变性，使我能够在新方向上扩展研究，学习新技术并获得建立独立实验室的知识和技能，专注于AD的表观遗传学。