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接受额外培训的疾病。为此， 多学科研究人员已组装，以帮助申请人进行培训和学习。 此外，参与波士顿大学医学院教师提供的计划 在申请人的主要院长之一的董事职务下的发展与多样性办公室将有助于 她在职业发展和过渡到独立方面。依据的机制 尚不清楚前进的年龄与心房颤动（AF）的关联尚不清楚。线粒体功能的下降具有 长期以来一直在衰老中发挥作用，但是线粒体遗传学和功能是否改变 与年龄相关的AF基础尚未得到彻底评估。整个基因组提供的更大的灵敏度 测序提供了评估MTDNA和AF中特定变化的新机会。我们假设 随着年龄的增长，线粒体DNA（mtDNA）突变的积累与A相对应 线粒体功能的下降促进了AF的发展。对于AIM 1，申请人将描述 NHLBI的多种族人口中的线粒体遗传多样性> 65,000名参与者 使用生物信息学注释和功能预测 mtDNA突变（Polyphen-2，预测，Mfold）。我们将评估mtDNA突变的关系和 拷贝数，年龄和AF的副本最高（AIM 2）。在AIM 3中，氧化磷酸化复合物 活动将以来自性别和合并症匹配的参与者的顶级生物循环样本进行测量 使用和不使用AIM 2（n = 150/组）与AF相关的变体，使用免疫接触， 分光光度测定。对MTDNA突变在AF中的贡献有更深入的了解将提供 可以在精确医学中使用的见解来识别特定药物目标的个体 和生活方式的变化旨在改变线粒体代谢和下游信号传导过程。这 K01提供的其他培训和受保护的时间将有助于申请人过渡到 独立研究者研究mtDNA，线粒体生理学和心血管的交叉点 疾病。