Ethnic-specific Effects of Mitochondrial DNA Variants and Environmental Factors on Cognitive Functioning and Dementia

线粒体 DNA 变异和环境因素对认知功能和痴呆的种族特异性影响

基本信息

批准号：
10397626
负责人：
EILEEN M CRIMMINS
金额：
$ 76.19万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-01 至 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10397626
关键词：
Affect African American population Age-Years Alzheimer&apos s Disease Alzheimer&apos s disease diagnosis Alzheimer&apos s disease related dementia Alzheimer&apos s disease risk Alzheimer&apos s disease therapeutic Amino Acid Sequence Amyloid beta-Protein Animals Attenuated Bioinformatics Blood Glucose Body mass index Brain Clinical Cognition DNA Data Dementia Diabetes Mellitus Diagnostic Education Encephalitis Environment Environmental Risk Factor Ethnic Origin Ethnic group Exhibits Gene Expression Genes Genetic Genetic Variation Health and Retirement Study High Fat Diet Hispanic Populations Human Impaired cognition Individual Initiator Codon Leukocytes Life Style Measures Meta-Analysis Metabolic Metabolic Diseases Mitochondria Mitochondrial DNA Mus Nature Neurodegenerative Disorders Not Hispanic or Latino Nuclear Obesity Participant Peptides Persons Physical activity Population Prefrontal Cortex Prevalence Process Publishing Race Reasons for Geographic And Racial Differences in Stroke Reporting Running Scanning Single Nucleotide Polymorphism Source Testing Tissues Translating United States Variant Weight Gain base caregiving clinical diagnosis clinical predictors cognitive function cohort cost design differential expression disease phenotype effective therapy ethnic difference ethnic diversity gene environment interaction gene interaction genetic analysis genetic association genome wide association study genome-wide genomic tools humanin improved insight lifestyle factors lifestyle intervention mitochondrial genome multi-ethnic new therapeutic target novel racial and ethnic disparities therapeutic target tool transcriptome sequencing transcriptomics

项目摘要

Among U.S race/ethnic groups over 75 years of age, African Americans exhibit the highest cognitive impairment prevalence (32%) followed by Hispanics (23%) and Non-Hispanic Whites (10%). Our proposal implements multiple novel genomic tools designed to capture ethnic-specific targets of Alzheimer's disease (AD) and related dementias (ADRD) within the mitochondrial DNA. A novel aspect of our proposal is that we can rapidly translate human mitochondrial genetic associations into cellular and animal experimental paradigms and infer whether these mtSNPs modify mitochondrial-derived peptides (MDPs), which are a group of micro-peptides that display profound effects on metabolic and neurodegenerative disease processes. We provide evidence in this proposal that we have already identified three mtSNPs in Non-Hispanic Whites, African Americans, and Hispanics that associate with AD phenotypes in an ethnic-specific fashion through MDPs. In this proposal, we will conduct several novel genetic analyses: (1) Mitochondrial Genome Wide Association Studies (MiWAS), (2) Mitochondrial Genome Wide GxE and GxG Interaction Studies (MiWIS), and (3) mitochondria RNASeq differential expression analysis (mito-transcriptomics), in three large, longitudinal multi-ethnic cohorts with comparable repeated measures of cognitive decline as well as lifestyle and metabolic factors (e.g., body mass index, diabetes, and physical activity). Using the Health and Retirement Study (HRS) and REasons for Geographic And Racial Differences in Stroke (REGARDS) cohorts, we will conduct discovery MiWAS and MiWIS for Non-Hispanic Whites (n~14,300), African Americans (n~13,400), and Hispanics (n~2,420). We will test replication of findings from HRS and REGARDS on cognitive decline and diagnosis of clinical AD using the diverse Rush Alzheimer's Disease Center (RADC) cohorts (n~4,500). We will conduct mito-transcriptomics for all ethnic groups in HRS (n~4,000; white blood cells) and in RADC (n~640; brain prefrontal cortex). Our central hypothesis is that specific mtSNPs and mitochondrial gene expression will predict clinical AD diagnosis and cognitive decline differently by ethnicity. For this project, we have assembled an interdisciplinary team to: 1) Identify ethnic-specific mtSNPs that predict cognitive decline, ADRD, and AD. 2) Identify ethnic-specific mtSNPs that interact with lifestyle factors or nuclear SNPs to affect cognitive decline, ADRD, and AD. 3) Investigate whether genes that encode mitochondrial-derived peptides are differentially expressed relative to AD or ADRD status in different ethnicities. This project permits discovery of mitochondrial genetic targets that can be explored as precision-based, ethnic-specific, potential ADRD treatment targets, in the form of micro-peptides derived from the mitochondria. Findings from this proposal will be instrumental to AD therapeutic discovery because the makeup of the national population is becoming more ethnically diverse.

在美国 75 岁以上的种族/族裔群体中，非裔美国人的认知障碍程度最高患病率（32%）其次是西班牙裔（23%）和非西班牙裔白人（10%）。我们的建议实施多种新颖的基因组工具旨在捕获阿尔茨海默病（AD）及相关疾病的种族特异性靶标线粒体DNA中的痴呆症（ADRD）。我们提案的一个新颖之处是我们可以快速翻译将人类线粒体遗传关联纳入细胞和动物实验范例并推断是否这些 mtSNP 修饰线粒体衍生肽 (MDP)，这是一组显示对代谢和神经退行性疾病过程产生深远影响。我们在此提案中提供证据我们已经在非西班牙裔白人、非裔美国人和西班牙裔中确定了三个 mtSNP 通过 MDP 以种族特定的方式与 AD 表型相关联。在本提案中，我们将进行几种新颖的遗传分析：(1) 线粒体全基因组关联研究 (MiWAS)，(2) 线粒体全基因组 GxE 和 GxG 相互作用研究 (MiWIS)，以及 (3) 线粒体 RNASeq 差异表达分析（线粒体转录组学），在三个大型纵向多种族队列中进行，具有可比较的重复认知能力下降以及生活方式和代谢因素（例如体重指数、糖尿病和体力活动）。使用健康与退休研究 (HRS) 以及地理和种族原因中风 (REGARDS) 队列的差异，我们将为非西班牙裔人群进行发现 MiWAS 和 MiWIS 白人 (n~14,300)、非裔美国人 (n~13,400) 和西班牙裔 (n~2,420)。我们将测试结果的重复性来自 HRS 和 REGARDS 的认知衰退和使用不同 Rush 阿尔茨海默病诊断临床 AD 的研究疾病中心 (RADC) 队列（n~4,500）。我们将在HRS中对所有族群进行线粒体转录组学研究（n~4,000；白细胞）和 RADC（n~640；大脑前额皮质）。我们的中心假设是具体的 mtSNP 和线粒体基因表达将以不同的方式预测临床 AD 诊断和认知能力下降种族。对于这个项目，我们组建了一个跨学科团队来：1) 识别种族特异性 mtSNP 预测认知能力下降、ADRD 和 AD。 2) 识别与生活方式因素相互作用的种族特异性 mtSNP 或核 SNP 影响认知能力下降、ADRD 和 AD。 3) 研究编码基因是否线粒体衍生肽在不同种族中相对于 AD 或 ADRD 状态的表达存在差异。该项目允许发现线粒体遗传目标，这些目标可以作为基于精确的、种族特异性的、潜在的 ADRD 治疗目标，以源自线粒体的微肽的形式。该提案的结果将有助于 AD 治疗的发现，因为国家的构成人口的种族变得更加多样化。