Relations of Mitochondrial Genetic Variation and Function with Atrial Fibrillation

线粒体遗传变异和功能与心房颤动的关系

• 批准号: 10374896
• 负责人: Jessica L Fetterman
• 金额: $ 15.23万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10374896
• 关键词: Adherence; Affect; Aging; Amino Acids; Animal Model; Applications Grants; Atrial Fibrillation; Bioinformatics; Biological Assay; Biology; Biometry; Blood Vessels; Boston; Calcium; Cardiovascular Diseases; Cardiovascular system; Cells; Clinical; Complex; DNA Damage; DNA Sequence Alteration; Data; Development; Elderly; Environment; Epidemiology; Framingham Heart Study; Future; Genetic; Genetic Variation; Genomics; Heart; Heart Atrium; Impairment; Individual; Inherited; Learning; Life Style; Link; Measures; Mediating; Mentors; Metabolic; Mitochondria; Mitochondrial DNA; Mutation; National Heart, Lung, and Blood Institute; Nuclear; Oxidative Phosphorylation; Oxidative Stress; Participant; Patients; Peptides; Persons; Pharmacologic Substance; Phenotype; Physiology; Play; Population; Postdoctoral Fellow; Process; Production; Proteins; RNA Folding; Research; Research Personnel; Risk Factors; Role; Sampling; Signal Transduction; Signaling Molecule; Teacher Professional Development; Testing; Time; Tissues; Training; Trans-Omics for Precision Medicine; Translational Research; Universities; Variant; age related; biobank; cardiometabolism; cardiovascular disorder risk; cell type; cohort; comorbidity; dietary; drug development; genetic epidemiology; genetic risk factor; genetic variant; genome sequencing; improved; induced pluripotent stem cell; insight; medical schools; mitochondrial DNA mutation; mitochondrial metabolism; multi-ethnic; multidisciplinary; new therapeutic target; novel; pre-doctoral; precision medicine; prevent; programs; protein function; sex; success; targeted treatment; trait; whole genome

Project Abstract The proposed study brings together the applicant's training in mitochondrial physiology and cardiovascular diseases with additional training in bioinformatics, biostatistics, and genetic epidemiology. To this end, a multidisciplinary team of investigators has been assembled to aid the applicant in her training and studies. Further, participation in the programs offered by the Boston University School of Medicine's Faculty Development and Diversity office under the directorship of one of the applicant's primary co-mentors will help her in her professional development and in transitioning to independence. The mechanisms underlying the association of advancing age with atrial fibrillation (AF) are unclear. Declines in mitochondrial function have long been appreciated to play a role in aging but whether alterations in mitochondrial genetics and function underlie age-related AF has not been thoroughly evaluated. The greater sensitivity afforded by whole genome sequencing provides novel opportunities to evaluate specific alterations in mtDNA and AF. We hypothesize that the accumulation of mitochondrial DNA (mtDNA) mutations with advancing age corresponds with a decline in mitochondrial function that promotes the development of AF. For Aim 1, the applicant will describe the mitochondrial genetic diversity within a multiethnic population of >65,000 participants within the NHLBI's Trans-Omics for Precision Medicine (TOPMed) using bioinformatics annotations and functional predictions of mtDNA mutations (PolyPhen-2, PredictSNP, MFold). We will assess the relations of mtDNA mutations and copy number with advancing age and AF in TOPMed (Aim 2). In Aim 3, oxidative phosphorylation complex activities will be measured in TOPMed biobanked samples from sex- and comorbidity-matched participants with and without the variants associated with AF from Aim 2 (N=150/group), using immunocapture, spectrophotometric assays. A greater understanding of the contribution of mtDNA mutations in AF will provide insights that could be utilized in precision medicine to identify individuals for specific pharmaceutical targets and lifestyle changes aimed at altering mitochondrial metabolism and downstream signaling processes. The additional training and protected time afforded by the K01 will aid the applicant in making her transition to an independent investigator studying the intersections of mtDNA, mitochondrial physiology, and cardiovascular disease.

项目摘要 拟议的研究汇集了申请人在线粒体生理学和心血管方面的培训 在生物信息学、生物统计学和遗传流行病学方面进行额外培训。为此，A 已经组建了一个多学科的调查小组，以帮助申请人进行培训和学习。 此外，参加波士顿大学医学院提供的课程 发展和多样性办公室根据申请人的主要共同导师之一的董事会将帮助 她的职业发展和过渡到独立。的作用机制 年龄增长与房颤（AF）的关系尚不清楚。线粒体功能的下降 长期以来，人们一直认为它在衰老中发挥作用，但线粒体遗传学和功能的改变是否 年龄相关性房颤的基础尚未得到全面评估。全基因组提供的更高灵敏度 测序提供了新的机会，以评估特定的改变，线粒体DNA和AF。 随着年龄的增长，线粒体DNA（mtDNA）突变的积累与 线粒体功能的下降促进AF的发展。 在NHLBI中，多种族人群中> 65，000名参与者的线粒体遗传多样性 使用生物信息学注释和功能预测的精准医学Trans-Omics（TOPMed） mtDNA突变（PolyPhen-2、PredictSNP、MFold）。我们将评估线粒体DNA突变与 拷贝数随着年龄的增长和AF在TOPMed（目标2）。在目标3中，氧化磷酸化复合物 将在性别和合并症匹配的受试者的TOPM生物库样本中测量活动 有和没有来自Aim 2的与AF相关的变体（N=150/组），使用免疫捕获， 分光光度测定对线粒体DNA突变在房颤中的作用的更深入的了解将提供 这些见解可用于精准医学，以识别特定药物靶点的个体 以及旨在改变线粒体代谢和下游信号传导过程的生活方式改变。的 K 01提供的额外培训和受保护的时间将帮助申请人过渡到 研究线粒体DNA，线粒体生理学和心血管疾病交叉点的独立研究者 疾病