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

• 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
• 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' s Disease; Alzheimer' s disease diagnosis; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Alzheimer' 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

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/民族群体中，非裔美国人表现出最高的认知障碍 患病率(32%)紧随其后的是西班牙裔(23%)和非西班牙裔白人(10%)。我们的建议实现了 多种新的基因组工具，旨在捕捉阿尔茨海默病(AD)及其相关的种族特定靶点 线粒体DNA中的痴呆(ADRD)。我们建议的一个新方面是，我们可以快速翻译 人类线粒体基因与细胞和动物实验范例的关联并推断 这些mtSNP修饰线粒体衍生的多肽(MDPs)，线粒体衍生的多肽是一组展示 对新陈代谢和神经退行性疾病过程产生深远影响。我们在这份提案中提供了证据 我们已经在非西班牙裔白人、非裔美国人和西班牙裔美国人中发现了三个mtSNPs 通过MDP以特定种族的方式与AD表型相关联。在这项提案中，我们将进行 几种新的遗传分析：(1)线粒体基因组广关联研究(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(有丝分裂转录组)，在三个具有可比重复的纵向多民族队列中 认知衰退的衡量标准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)。使用健康和退休研究(HRS)以及地理和种族原因 卒中(关于)队列的差异，我们将为非西班牙裔进行MIWA和MIWIS发现 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 不同类型Rush阿尔茨海默病对认知功能减退及临床诊断的影响 疾病中心(RADC)队列(n~4,500)。我们将在HRS为所有民族进行有丝分裂转录 RADC区(n~640；大脑前额叶皮质)。我们的中心假设是特定的 线粒体SNPs和线粒体基因表达将通过不同的方式预测临床AD诊断和认知能力下降 种族问题。为了这个项目，我们组建了一个跨学科的团队：1)确定特定种族的mtSNPs 可以预测认知功能减退、ADRD和AD。2)确定与生活方式因素相互作用的特定种族的mtSNP 或影响认知功能减退、ADRD和AD的核SNP。3)调查编码基因是否 线粒体衍生的多肽在不同种族中的表达与AD或ADRD状态有关。 该项目允许发现线粒体基因靶标，这些基因靶标可以被探索为基于精确的， 种族特定、潜在的ADRD治疗靶点，其形式为源自线粒体的微肽。 这项提案的发现将有助于AD治疗的发现，因为国家 人口的种族多样性正在变得更加多样化。