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：
10031382
负责人：
EILEEN M CRIMMINS
金额：
$ 58.09万
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/10031382
关键词：
Affect African American 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 Hispanics 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 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 new therapeutic target novel racial and ethnic disparities therapeutic target tool transcriptome sequencing transcriptomics

Affect African American 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 Hispanics 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 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 new therapeutic target novel racial and ethnic disparities therapeutic target tool transcriptome sequencing transcriptomics

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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75岁以上的美国种族/族裔中，非裔美国人表现出最大的认知障碍患病率（32％），其次是西班牙裔（23％）和非西班牙裔白人（10％）。我们的提议实施多种新型基因组工具，旨在捕获阿尔茨海默氏病（AD）及相关的特定民族靶标线粒体DNA中的痴呆症（ADRD）。我们提案的一个新颖方面是我们可以迅速翻译人的线粒体遗传关联与细胞和动物实验范例，并推断这些MTSNP修饰线粒体衍生的肽（MDPS），它们是一组显示的微肽对代谢和神经退行性疾病过程的深刻影响。我们在此提案中提供证据我们已经确定了非西班牙裔白人，非裔美国人和西班牙裔的三个MTSNP 通过MDP以特定于种族的方式与AD表型相关联。在此提案中，我们将进行几种新的遗传分析：（1）线粒体基因组广泛的关联研究（MIWAS），（2）线粒体基因组宽GXE和GXG相互作用研究（MIWIS）和（3）线粒体RNASEQ差异表达分析（Mito-Transcriptomics），在三个大型的，纵向的多族裔队列中，具有可比的重复认知能力下降以及生活方式和代谢因素的度量（例如，体重指数，糖尿病和体育锻炼）。使用健康和退休研究（HRS）以及地理和种族的原因中风差异（有关）队列的差异，我们将进行非西班牙裔Miwas和Miwis 白人（N〜14,300），非裔美国人（N〜13,400）和西班牙裔（n〜2,420）。我们将测试发现的复制从HRS和关于使用多样的Rush Alzheimer的认知能力下降和诊断临床AD的诊断的问候疾病中心（RADC）队列（N〜4,500）。我们将为HRS的所有种族群体进行Mito-Transcriptomics （N〜4,000;白细胞）和RADC（N〜640;脑前额叶皮层）。我们的中心假设是 MTSNP和线粒体基因表达将通过种族。对于这个项目，我们组装了一个跨学科团队：1）确定特定民族的MTSNP 这可以预测认知能力下降，ADRD和AD。 2）确定与生活方式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）研究是否编码的基因线粒体衍生的肽相对于不同种族的AD或ADRD状态差异表达。该项目允许发现线粒体遗传靶标，可以探讨基于精确的，种族特异性的，潜在的ADRD治疗靶标，是源自线粒体的微肽的形式。该提案的发现将有助于AD治疗发现，因为国家的构成人口正在变得越来越多样化。