Interplay between Mitochondrial DNA Haplogroups, Mitochondrial Function, Oxidative Stress, and Hypertension

线粒体 DNA 单倍群、线粒体功能、氧化应激和高血压之间的相互作用

• 批准号: 10250869
• 负责人: michele k evans
• 金额: $ 97.84万
• 依托单位: NATIONAL INSTITUTE ON AGING
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10250869
• 关键词: Affect; African; African American; Age; Aging; Baltimore; Blood Circulation; Cardiovascular Diseases; Caucasians; Cell Line; Cells; Cities; Cohort Studies; Complementarity Determining Regions; DNA; DNA Damage; DNA Sequence; DNA copy number; Data; Development; Disease; Follow-Up Studies; Gene Expression; Genes; Genetic Polymorphism; Genetic Recombination; Genetic Transcription; Haplogroup; Haplotypes; Health; Histones; Human; Hypertension; Incidence; Individual; Inflammation; Inherited; Introns; Investigation; Knowledge; Link; Longevity; Longitudinal Studies; Messenger RNA; Mission; Mitochondria; Mitochondrial DNA; Molecular; Morbidity - disease rate; Mutation; Neighborhoods; Nuclear; Oxidative Stress; Participant; Pathway interactions; Pattern; Phylogenetic Analysis; Play; Poly(ADP-ribose) Polymerases; Population; Population Heterogeneity; Poverty; Prevalence; Proteins; Race; Reactive Oxygen Species; Reporting; Research; Research Personnel; Rest; Risk; Risk Factors; Role; Socioeconomic Status; Tissue-Specific Gene Expression; Trees; United States; Untranslated RNA; Variant; Woman; Work; age related; cardiovascular disorder risk; cell community; cell immortalization; cohort; differential expression; ethnic diversity; health disparity; healthy aging; human migration; middle age; mitochondrial dysfunction; mortality; normotensive; novel; oxidative damage; racial and ethnic; racial difference; racial diversity; sensor; sex; social; social health determinants; transcriptome

Thus far, there are few studies that examine the contribution of mtDNA haplogroup to differences in risk factors for age-related health disparities such as in hypertension. The Healthy Aging in Neighborhoods of Diversity across the Life Span (HANDLS) study examines the interaction of race and socioeconomic status on the development of age-associated health disparities among middle-aged AAs and whites residing in Baltimore City. It is possible that population differences in haplogroups could contribute to disparities in mitochondrial function and oxidative stress, and thus contribute to hypertension health disparities. Therefore, we hypothesize that mtDNA haplogroups will influence the presence of age-associated health disparities in hypertension among AAs and whites in the HANDLS cohort and will correlate with mitochondrial health and function. We also predict that mitochondrial health and function will be further influenced by poverty status and other social determinates of health. Establishing whether mtDNA haplogroups influence mitochondrial function and hypertension will contribute to the understanding of population disparities in age-related diseases, and thus this proposal is highly aligned with the NIA mission. Preliminary Results: Previously, we reported racial differences in the transcriptome of HANDLS participants with or without hypertension. Interestingly, in these hypertensive and normotensive women there were significant differential expression in hypertension and inflammation-related mRNAs. In a follow up study of this cohort of women, we found that there were higher levels of the DNA damage sensor protein poly-(ADP-ribose) polymerase 1 (PARP1) in AA women with hypertension compared to normotensive AA women. PARP1 levels were also higher in AA women with hypertension compared to white hypertensive women. Since PARP1 is involved in oxidative stress, these data suggest that differential PARP1 expression might play a role in hypertension-related health disparities. These data indicate that there is differential gene expression by hypertension and race in HANDLS participants, which may influence oxidative stress levels. Importantly, recent research suggests that mtDNA haplogroup can affect both mitochondrial function, transcription of mitochondrial genes, and also nuclear gene expression. However, most studies are performed in immortalized cell lines, especially artificially created cybrid lines. Few studies investigate the changes in mitochondrial function or damage in cells from community-dwelling individuals. In addition, few studies have examined whether hypertension is correlated with a specific mtDNA haplogroup in a racially diverse cohort. Examining the relationship between mtDNA haplogroups, hypertension, and differences in mitochondrial function and oxidative damage will lead to a greater understanding of mitochondrial connection in aging and age-related health disparities. Our specific aims for this project will include: Aim 1: SNP haplotyping of HANDLS cohort of hypertensive participants, Aim 2: Examine the impact of haplogroup on mitochondrial function and oxidative damage in a hypertension subset within the context of race and selected social determinants of health and Aim 3: Examine the impact of haplogroup on oxidative damage to nuclear DNA in a hypertension subset within the context of race and selected social determinants of health.

到目前为止，很少有研究探讨mtDNA单倍型群对年龄相关的健康差异（如高血压）的危险因素差异的贡献。健康老龄化在整个生命周期的多样性社区（HANDLS）研究探讨了种族和社会经济地位的相互作用，对中年AA和居住在巴尔的摩市的白人之间与年龄相关的健康差异的发展。单倍型组的人群差异可能导致线粒体功能和氧化应激的差异，从而导致高血压健康差异。因此，我们假设mtDNA单倍型群将影响HANDLS队列中AA和白人高血压中年龄相关健康差异的存在，并与线粒体健康和功能相关。我们还预测，线粒体的健康和功能将进一步受到贫困状况和其他社会健康决定因素的影响。确定线粒体DNA单倍型群是否影响线粒体功能和高血压将有助于理解年龄相关疾病的人群差异，因此这一提议与NIA的使命高度一致。 初步结果： 以前，我们报道了HANDLS参与者的转录组有或没有高血压的种族差异。有趣的是，在这些高血压和血压正常的妇女中，高血压和炎症相关的mRNA表达存在显着差异。在对这组女性的随访研究中，我们发现，与血压正常的AA女性相比，患有高血压的AA女性的DNA损伤传感器蛋白聚（ADP-核糖）聚合酶1（PARP 1）水平较高。与白色高血压女性相比，AA高血压女性的PARP 1水平也更高。由于PARP 1参与氧化应激，这些数据表明，差异PARP 1表达可能在高血压相关的健康差异中发挥作用。这些数据表明，在HANDLS参与者中，高血压和种族存在差异基因表达，这可能会影响氧化应激水平。 重要的是，最近的研究表明，mtDNA单倍型群可以影响线粒体功能，线粒体基因的转录，以及核基因的表达。然而，大多数研究都是在永生化细胞系中进行的，特别是人工创建的cybrid系。很少有研究调查线粒体功能的变化或来自社区居住个体的细胞损伤。此外，很少有研究探讨高血压是否与种族多样性队列中特定mtDNA单倍型组相关。研究线粒体DNA单倍型群，高血压，线粒体功能和氧化损伤的差异之间的关系将导致衰老和年龄相关的健康差异的线粒体连接的更好的理解。 本项目的具体目标包括：目标1：HANDLS高血压参与者队列的SNP单倍型分型，目标2：在种族和选定的健康社会决定因素的背景下，检查单倍型组对高血压亚组中线粒体功能和氧化损伤的影响，目标3：在种族和选定的健康社会决定因素的背景下，检查单倍型对高血压亚组细胞核DNA氧化损伤的影响。