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 脑动脉硬化症（B-ASC）是一种脑血管疾病，其特征是脑动脉病理性增厚 大脑中的小动脉，包括 B-ASC 在内的非阿尔茨海默病脑部病变越来越多。 在尸检队列中，B-ASC 被认为是导致老年人认知能力下降的重要因素。 发现超过 50% 的 80 岁或以上的参与者死亡时 B-ASC 与多种其他因素相关。 神经病理学，包括海马硬化，尽管具有临床重要性，但大脑的病理生理学。 动脉硬化及其与其他病理的机制关系尚不清楚。 四个高质量神经病理学队列之间汇总和协调的基因型和尸检数据： 国家阿尔茨海默病协调中心 (NACC)、宗教秩序研究以及记忆与衰老 项目 (ROSMAP)、成人思维变化研究 (ACT) 和阿尔茨海默病神经影像学 主动神经病理学队列 (ADNI) 进行初步遗传关联和功能基因组研究。 通过 NACC 参与者，我们确定了多个 B-ASC 风险位点，这些位点在至少一个独立的 队列并建立了神经病理内表型 (NPE) 的遗传学研究框架。 我们追求利用基因表达和 DNA 甲基化进行分析来进一步表征 B-ASC 病理学的基因组危险因素 我们将研究 B-ASC 与基因之间的关系。 使用 ROSMAP 进行背外侧前额皮质的表达和 DNA 甲基化分析。 其次是计算方法，将估计不同细胞类型的贡献并预测基因 在目标 2 中，我们追求 B-ASC 与其他队列的基因型数据共享基因组风险。 我们将首先使用我们已建立的分析流程来进行遗传关联研究。 NPE 与 B-ASC 共病，然后我们将使用统计方法来量化和定位共同的遗传风险。 这些研究的结果将提供 B-ASC 的严格表征。 我们的跨性状分析将有助于阐明 B-ASC 在该疾病中的地位。 我的导师和合作者中常见的混合大脑病理的复杂网络。 招募的团队由经验丰富的多学科团队组成，其中包括两名生物统计学家、一名遗传学家 流行病学家和实验神经病理学家。 NIH F30 奖学金将提供必要的条件。 作为临床医生，为我职业生涯的下一阶段做好准备所必需的经验、知识和技能 研究员。