Elucidating Shared Risk of Brain Arteriolosclerosis and Related Pathologies with Multiple 'omics Modalities

通过多种组学模式阐明脑动脉硬化及相关病理的共同风险

• 批准号: 10759365
• 负责人: Lincoln Shade
• 金额: $ 5.27万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-08 至 2025-07-07
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10759365
• 关键词: Adult; Age; Aging; Alzheimer' s Disease; Architecture; Autopsy; Bioinformatics; Biological; Biological Assay; Brain; Brain Pathology; Cells; Cerebrovascular Disorders; Cerebrovascular system; Cessation of life; Chromosomes; Clinical; Clinical Research; Cognitive; Complex; DNA Methylation; Data; Data Set; Dementia; Development; Diabetes Mellitus; Disease; Epidemiologist; Fellowship; Functional disorder; Gene Expression; Generations; Genetic; Genetic Risk; Genetic study; Genomics; Genotype; Hypertension; Impaired cognition; Individual; Internet; Knowledge; Memory; Mentors; Methods; Methylation; Modality; Molecular; Multiomic Data; Outcome; Participant; Pathologic; Pathology; Pathway interactions; Phenotype; Pilot Projects; Prefrontal Cortex; Preparation; Process; Research; Research Personnel; Resources; Risk; Risk Factors; Sampling; Source; Statistical Methods; Testing; Training Programs; Translating; United States National Institutes of Health; Update; aged; arteriole; brain arteriolosclerosis; career; case control; cell type; clinical risk; cohort; comorbidity; design; endophenotype; experience; functional genomics; genetic association; genetic risk factor; genome wide association study; genome-wide; hippocampal sclerosis; human old age (65+); insight; molecular phenotype; multidisciplinary; multiple omics; neuroimaging; neuropathology; new therapeutic target; recruit; religious order study; risk sharing; risk variant; skills; therapeutic target; trait; translational genomics

Abstract Brain arteriolosclerosis (B-ASC) is a cerebrovascular disease characterized by pathological thickening of the arterioles in the brain. Non-Alzheimer’s disease brain pathologies, including B-ASC, are increasingly recognized as important contributors to cognitive decline in aged individuals. In autopsy cohorts, B-ASC is found in over 50% of participants aged eighty years or older at death. B-ASC is associated with multiple other neuropathologies, including hippocampal sclerosis. Despite its clinical importance, the pathophysiology of brain arteriolosclerosis and its mechanistic relationship to other pathologies are not well understood. We have aggregated and harmonized genotype and autopsy data between four high-quality neuropathology cohorts: the National Alzheimer’s Coordinating Center (NACC), the Religious Orders Study and the Memory and Aging Project (ROSMAP), the Adult Changes in Thought Study (ACT), and the Alzheimer’s Disease Neuroimaging Initiative Neuropathology Cohort (ADNI). In preliminary genetic association and functional genomic studies using NACC participants, we identified multiple B-ASC risk loci that replicated in at least one independent cohort and established a framework for genetic studies of neuropathological endophenotypes (NPE). In Aim 1, we hypothesize that analyses employing gene expression and DNA methylation will further characterize genomic risk factors for B-ASC pathology. We will investigate the relationship between B-ASC, gene expression, and DNA methylation in the dorsolateral prefrontal cortex using ROSMAP. These analyses will be followed by computational approaches that will estimate the contribution of different cell types and predict gene expression from genotype data in other cohorts. In Aim 2, we hypothesize that B-ASC shares genomic risk with associated NPE. We will first use our established analytic pipeline to perform genetic association studies of NPE comorbid with B-ASC. We will then use statistical methods to quantify and localize shared genetic risk between B-ASC and other NPE. Findings from these studies will provide a rigorous characterization of B-ASC risk factors and relevant biological pathways. Our cross-trait analyses will help clarify B-ASC’s place in the complex web of mixed brain pathologies common in aged individuals. The mentors and collaborators I have recruited comprise an experienced and multidisciplinary team that includes two biostatisticians, a genetic epidemiologist, and an experimental neuropathologist. This NIH F30 fellowship will provide the requisite experience, knowledge, and skills necessary as preparation to the next stage in my career as a clinical researcher.

抽象的 脑动脉粥样硬化（B-ASC）是一种脑血管疾病，其特征在于病理增厚 大脑中的小动物。包括B-ASC在内的非阿尔茨海默氏病脑病理学越来越多 被认为是老年人认知下降的重要贡献者。在尸检队列中，B-ASC是 在50％以上的八十岁以上的参与者中发现。 B-ASC与其他多个 神经病理学，包括海马硬化症。尽管其临床重要性，但大脑的病理生理学 小动脉硬化及其与其他病理的机械关系尚不清楚。我们有 四个高质量神经病理学队列之间的汇总和统一基因型和尸检数据： 国家阿尔茨海默氏症协调中心（NACC），宗教命令研究以及记忆与老化 项目（Rosmap），成人思想研究（ACT）的变化和阿尔茨海默氏病神经影像学 倡议神经病理学队列（ADNI）。在初步遗传关联和功能基因组研究中 使用NACC参与者，我们确定了至少一个独立的多个B-ASC风险基因座 队列并建立了神经病理内表型（NPE）的遗传研究框架。在AIM 1中， 我们假设采用基因表达和DNA甲基化的分析将进一步表征 Basc病理学的基因组危险因素。我们将研究B-ASC，基因之间的关系 使用Rosmap在背外侧前额叶皮层中的表达和DNA甲基化。这些分析将是 然后采用计算方法，以估计不同细胞类型的贡献并预测基因 来自其他队列中基因型数据的表达。在AIM 2中，我们假设B-ASC与 相关的NPE。我们将首先使用我们已建立的分析管道进行遗传关联研究 NPE合并与B-ASC。然后，我们将使用统计方法来量化和本地化共享的遗传风险 在B-ASC和其他NPE之间。这些研究的发现将提供B-ASC的严格特征 风险因素和相关的生物途径。我们的跨特征分析将有助于Clariy B-ASC在 在老年人中常见的混合脑病理学的复杂网络。我拥有的导师和合作者 招募完成了一个经验和多学科团队，其中包括两个生物统计学家，一个通用 流行病学家和实验性神经病理学家。这项NIH F30奖学金将提供必要的 作为临床职业生涯的下一阶段所必需的经验，知识和技能 研究员。