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: 10594477
• 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/10594477
• 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 Sequence Alteration; Data; Development; Elderly; Environment; Epidemiology; Ethnic Population; 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; Phosphorylation; Physiology; Postdoctoral Fellow; Process; Production; RNA Folding; Research; Research Personnel; Risk Factors; 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 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 并接受生物信息学、生物统计学和遗传流行病学方面的额外培训。为此，一个 已经组建了多学科研究小组来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员提供的课程 由申请人的主要共同导师之一领导的发展和多样性办公室将提供帮助 她的职业发展和向独立的过渡。其背后的机制 年龄增长与心房颤动（AF）之间的关系尚不清楚。线粒体功能下降 长期以来人们一直认为线粒体在衰老过程中发挥着作用，但线粒体遗传学和功能是否发生改变 年龄相关性房颤的潜在原因尚未得到彻底评估。全基因组提供更高的灵敏度 测序为评估 mtDNA 和 AF 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）突变的积累与 线粒体功能下降促进房颤的发生。对于目标 1，申请人将描述 NHLBI 内超过 65,000 名参与者的多种族群体中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组学 (TOPMed) mtDNA 突变（PolyPhen-2、PredictSNP、MFold）。我们将评估 mtDNA 突变与 TOPMed 中随年龄增长和 AF 变化的拷贝数（目标 2）。在目标 3 中，氧化磷酸化复合物 活动将在来自性别和合并症匹配参与者的 TOPMed 生物库样本中进行测量 使用免疫捕获，使用或不使用目标 2 中与 AF 相关的变异（N=150/组）， 分光光度测定。更好地了解 mtDNA 突变在 AF 中的作用将有助于 可用于精准医学的见解，以识别特定药物目标的个体 生活方式的改变旨在改变线粒体代谢和下游信号传导过程。这 K01 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 mtDNA、线粒体生理学和心血管交叉点的独立研究者 疾病。

项目成果

Teamwork makes the dream work: functional collaborations between families, scientists, and healthcare providers to drive progress in the treatment of Leigh Syndrome.

• DOI: 10.1186/s13023-023-02871-7
• 发表时间: 2023-11-16
• 期刊: ORPHANET JOURNAL OF RARE DISEASES
• 影响因子: 3.7
• 作者: Moreira, Jesse D.;Smith, Karan K.;Zilber, Sophia;Woleben, Kasey;Fetterman, Jessica L.
• 通讯作者: Fetterman, Jessica L.

Moralization of E-cigarette Use and Regulation: A Mixed-Method Computational Analysis of Opinion Polarization.

电子烟使用和监管的道德化：意见极化的混合方法计算分析。

• DOI: 10.1080/10410236.2022.2027640
• 发表时间: 2023
• 期刊: Health communication
• 影响因子: 3.9
• 作者: Wang,Yunwen;Xu,YusiAveva;Wu,Jiaxi;Kim,HyeMin;Fetterman,JessicaL;Hong,Traci;McLaughlin,MargaretL
• 通讯作者: McLaughlin,MargaretL

The Mighty NUMT: Mitochondrial DNA Flexing Its Code in the Nuclear Genome.

• DOI: 10.3390/biom13050753
• 发表时间: 2023-04-27
• 期刊: Biomolecules
• 影响因子: 5.5