Genetic Contributors to White Matter Microstructure in Aging and Alzheimers Disease

衰老和阿尔茨海默病中白质微结构的遗传因素

• 批准号: 10459610
• 负责人: Derek B Archer
• 金额: $ 12.02万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10459610
• 关键词: Academic Medical Centers; Accounting; Aging; Alzheimer disease prevention; Alzheimer' s Disease; Alzheimer' s disease risk; Architecture; Area; Atrophic; Automobile Driving; Award; Axonal Transport; Baltimore; Big Data Methods; Biological; Brain; Candidate Disease Gene; Career Mobility; Clinical; Cognitive; Complex; Data; Data Analyses; Data Set; Diffusion Magnetic Resonance Imaging; Ensure; Environment; Evaluation; Extracellular Space; Foundations; Functional disorder; Funding; Future; Gene Expression; Genes; Genetic; Genetic Diseases; Genetic Techniques; Genetic study; Genomics; Goals; Image; Impaired cognition; Intracellular Space; Laboratories; Lead; Longevity; Longitudinal Studies; Longitudinal cohort; Measurement; Medial; Mediating; Memory; Mentors; Minority; Modeling; Molecular; Nerve Degeneration; Neurodegenerative Disorders; Oligodendroglia; Participant; Pathway Analysis; Pathway interactions; Positioning Attribute; Process; Registries; Research; Resolution; Resources; Role; Senile Plaques; Signal Transduction; Techniques; Temporal Lobe; Testing; Tissues; Training; Validation; Variant; Water; Wisconsin; Work; base; biobank; career; career development; catalyst; cohort; data harmonization; genetic analysis; genetic architecture; genetic variant; genome wide association study; genome-wide; genome-wide analysis; gray matter; hippocampal atrophy; imaging genetics; in vivo; large scale data; multidisciplinary; myelination; neuroimaging; neuroinflammation; new therapeutic target; novel; polygenic risk score; pre-clinical; professor; religious order study; research and development; research study; risk variant; skills; tau aggregation; tractography; trait; white matter; white matter damage

PROJECT SUMMARY While reductions in medial temporal lobe (MTL) white matter tract microstructure have been suggested to have a central role in longitudinal cognitive decline in aging and Alzheimer’s disease (AD), it is unknown what genetic factors drive these reductions. The objective of this proposal is to use MTL white matter tract templates in conjunction with genome-wide analyses to identify the genetic drivers of white matter tract microstructure. This proposal will leverage several aging datasets, including the Alzheimer’s Disease Neuroimaging Initiative (n=525), Baltimore Longitudinal Study of Aging (n=295), Religious Orders Study/Memory and Aging Project/Minority Aging Research Study (n=414), Vanderbilt Memory & Aging Project (n=319), Wisconsin Alzheimer’s Disease Research Center (n=488), and Wisconsin Registry for Alzheimer’s Prevention (n=468) to conduct all analyses, totaling in 2,509 participants. Moreover, validation of all results will be conducted using data from a well-established lifespan study (UK Biobank (n=14,701)) and data from the AD Genetics Consortium. The central hypothesis is that MTL white matter tract microstructure is driven by genes and pathways related to myelination, axonal transport, and neuroinflammation in aging and AD. Based on this hypothesis, the primary aims of this proposal will take a multi-level approach to understand which genes and pathways lead to MTL white matter microstructure by using: (1) a candidate gene approach to determine with AD-risk genes are associated with MTL white matter microstructure, (2) a genome-wide approach to identify novel variants which contribute to MTL white matter microstructure and quantify genetic overlap with other traits, and (3) a genome-wide approach to identify how gene expression is associated with MTL white matter tract microstructure and localize signals to relevant biologic pathways. The complementary training plan will equip me with the skills necessary to transition to an independent career focused on imaging genetics by emphasizing the following training objectives: (a) expand expertise in computational genetics, (b) acquire a practical understanding of the pathophysiology and clinical manifestation of AD, and (c) enhance my skillset in data harmonization and big data analytical techniques. The mentoring team is made up of experts in each of these areas, and their training will be augmented through formal coursework, interdisciplinary training at the Vanderbilt Memory & Alzheimer’s Center, and cutting-edge computational and genomic resources available at the Vanderbilt University Medical Center. Together, these practical and intellectual resources provide the ideal training environment, and my primary mentor, Dr. Timothy Hohman, has a well-funded laboratory which will provide all the necessary resources for career transition. These resources will allow me to dedicate 100% protected effort as an Assistant Professor to focus on research and career development. This will ensure that I can competitively compete for independent funding (R01) over the course of the proposed award period.

项目摘要 虽然已经建议减少内侧临时叶（MTL）白质微观结构 在衰老和阿尔茨海默氏病（AD）的纵向认知下降中的核心作用，尚不清楚什么 遗传因素驱动这些减少。该提案的目的是使用MTL白质模板 结合全基因组分析，以鉴定白质微观结构的遗传驱动因素。 该建议将利用几个老化数据集，包括阿尔茨海默氏病神经影像学计划 （n = 525），巴尔的摩衰老纵向研究（n = 295），宗教秩序研究/记忆和老化 项目/少数民族老化研究（n = 414），范德比尔特记忆与老化项目（n = 319），威斯康星州 阿尔茨海默氏病研究中心（n = 488）和威斯康星州的阿尔茨海默氏症登记处（n = 468） 进行所有分析，总计2,509名参与者。此外，所有结果的验证将使用 一项良好的寿命研究（UK Biobank（n = 14,701））和AD遗传学数据的数据 财团。中心假设是MTL白质公司微观结构是由基因驱动的， 与髓鞘，轴突运输和衰老和AD中的神经炎症有关的途径。基于此 假设，该提案的主要目的将采用多层次的方法来了解哪些基因和哪些基因 通过使用：（1）确定与 广告风险基因与MTL白质微观结构有关，（2）识别全基因组的方法 新型变体有助于MTL白质微观结构并量化与其他的遗传重叠 特征和（3）全基因组的方法来识别基因表达如何与MTL白质有关 道微结构并将信号定位于相关的生物学途径。完整的培训计划将 为我配备过渡到专注于成像遗传学的独立职业所需的技能 强调以下培训目标：（a）扩大计算遗传学方面的专业知识，（b）获取 对AD的病理生理学和临床表现的实际理解，以及（c）提高我的技能 数据协调和大数据分析技术。心理团队由专家组成 这些领域以及他们的培训将通过正式的课程，跨学科培训来增强 Vanderbilt Memory＆Alzheimer的中心以及尖端的计算和基因组资源可在 范德比尔特大学医学中心。这些实用和智力资源共同提供了理想 培训环境，我的主要导师蒂莫西·霍曼（Timothy Hohman）有一个资金良好的实验室 为职业过渡提供所有必要的资源。这些资源将使我能够100％专用 作为助理教授的保护，专注于研究和职业发展。这将确保我 在拟议奖励期间，可以有能力争夺独立资金（R01）。