Relations of Mitochondrial Genetic Variation and Function with Atrial Fibrillation

项目摘要 拟议的研究将申请者在线粒体生理学和心血管方面的培训结合在一起 在生物信息学、生物统计学和遗传流行病学方面的额外培训。为此，一个 已经组建了多学科的调查小组，以帮助申请者进行培训和学习。 此外，参加波士顿大学医学院提供的课程 在申请人的一名主要共同导师的指导下，发展和多样性办公室将提供帮助 在她的职业发展和向独立过渡的过程中，她取得了巨大的进步。其背后的机制是 增龄与房颤(房颤)的关系尚不清楚。线粒体功能的下降有 长期以来，人们一直认为线粒体在衰老中起作用，但线粒体遗传和功能的改变 潜在的年龄相关性房颤尚未得到彻底的评估。全基因组提供的更高的敏感度 测序为评估线粒体DNA和房颤的特定改变提供了新的机会。我们假设 随着年龄的增长，线粒体DNA(MtDNA)突变的积累符合 线粒体功能的下降促进了房颤的发展。对于目标1，申请者将描述 NHLBI内65,000名多民族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跨基因组学(TOPMed) 线粒体DNA突变(PolyPhen-2、前SNP、MFold)。我们将评估线粒体DNA突变与 在TOPMed(目标2)中，随着年龄的增长和房颤的增加而复制数量。在目标3中，氧化磷酸化复合体 活动将在TOPMed生物库样本中进行测量，样本来自性别和合并症匹配的参与者 使用免疫捕获技术，使用与来自AIM 2(N=150个/组)的房颤相关的变体， 分光光度分析。更好地理解线粒体DNA突变在房颤中的作用将提供 可用于精确医学以识别特定药物靶点的个人的见解 以及旨在改变线粒体新陈代谢和下游信号传递过程的生活方式改变。这个 K01提供的额外培训和受保护的时间将有助于申请人过渡到 独立研究员，研究线粒体DNA、线粒体生理学和心血管的交叉 疾病。

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.