Training in Molecular Epidemiology: Linking Genes to Physical Function in Older Adults

分子流行病学培训：将基因与老年人的身体功能联系起来

• 批准号: 9908039
• 负责人: Adam J Santanasto
• 金额: $ 11.64万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9908039
• 关键词: Address; Adopted; Aerobic; Aged, 80 and over; Aging; Animals; Area; Award; Bioinformatics; Biological; Biological Assay; Biological Markers; Biological Process; Biology of Aging; Biometry; Blood; Body Weight decreased; Cell Culture Techniques; Cells; Clinical; Cohort Analysis; Consultations; DNA; Data; Elderly; Enzyme-Linked Immunosorbent Assay; Epidemiologic Methods; Epidemiologist; Epidemiology; Equilibrium; Expression Profiling; Family; Family Study; Fibrosis; Foundations; Functional disorder; Funding; Gene Proteins; Genes; Genetic; Genetic Polymorphism; Genetic Transcription; Genomic Segment; Geroscience; Health Care Costs; Healthcare; Heart; Heart failure; Human; Human Genetics; Impairment; Institutionalization; Intervention; Investments; K-Series Research Career Programs; Knowledge; Lead; Life; Life Style; Link; Liver diseases; Longevity; Maps; Measures; Mentors; Mentorship; Messenger RNA; Meta-Analysis; Methods; Mitochondria; Molecular; Molecular Biology; Molecular Epidemiology; Multicenter Studies; Muscle; Myocardial; N-terminal; Natural regeneration; Pathogenicity; Pathway interactions; Phenotype; Physical Function; Physical activity; Plasma; Plasma Proteins; Population; Positioning Attribute; Postdoctoral Fellow; Procollagen; Proteins; Public Health; RNA; Research; Research Personnel; Research Training; Role; Sampling; Serum; Severity of illness; Signal Transduction; Signaling Protein; Skeletal Muscle; TGF Beta Signaling Pathway; Testing; Tissues; Training; Transducers; Transforming Growth Factor beta; United States National Institutes of Health; Walking; age related; age-related muscle loss; base; biomarker development; career; cohort; density; design; disability; epidemiology study; follow-up; functional decline; genetic epidemiology; genetic linkage analysis; genetic variant; genome wide association study; genome-wide; genome-wide linkage; genomic epidemiology; high risk; improved; innovation; insight; intervention effect; lifestyle intervention; mRNA Expression; mortality; muscle aging; novel; potential biomarker; premature; prevent; protein biomarkers; skeletal muscle differentiation; skills; statistics; strength training; therapeutic target

Age-related declines in physical function are common and lead to increased health care costs, institutionalization and mortality. As a traditional epidemiologist with unique expertise in skeletal muscle aging and physical function, I have researched lifestyle interventions (weight loss, aerobic and resistance training) to prevent age-related declines in physical function. However, lifestyle changes are difficult to adopt, especially for those at the highest risk for functional decline. To extend the benefits of these interventions, it is imperative to understand biological processes underlying changes in function with aging and following intervention. As such, the current proposal will provide the candidate with advanced training in molecular epidemiology and biology of aging, yield novel insight on the genetic and biological basis of physical function among older adults and lay the foundation for future research. Specially, Aim 1 will identify genes and genetic variants for physical function and changes in physical function with aging. Aim 2 will examine blood RNA expression for components of the transforming growth factor beta (TGF-β) pathway, which is implicated in muscle dysfunction and pathogenic fibrosis, with physical function and its change with aging. Aim 3 will test if serum levels of TGF-β and procollagen type 3 N- terminal propeptide (P3NP - a biomarker of pathogenic fibrosis) are related physical function among older adults. I will leverage robustly collected physical function measures, biological samples, and an ultra-high-density genome-wide polymorphism map from the NIA-funded Long Life Family Study (LLFS), a multi-center study of exceptional aging and longevity in families and from The Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium . The proposed research and training is very innovative. First, despite being implicated in several age-related conditions there have been no human studies that have examined the relationship between TGF-β or P3NP and physical function. Further, LLFS has a large number of “oldest old”, who are understudied and at the highest risk for functional decline. There has also been limited research on the genetics of physical function. The proposed career development award will provide the applicant with essential new mentorship, knowledge and skills in human genetics and molecular epidemiology including but not limited to blood RNA expression and protein biomarker development (Aim 2 and 3), genome wide association (GWA) and linkage analyses (Aim 1 ), meta-analysis (Aim 1) and bioinformatics (Aim 1) approaches to follow-up association and linkage analyses. Finally, this award will be critical for facilitating my transition to an independent research career in aging and molecular epidemiology with a focus on physical function. As an epidemiologist with expertise in both traditional and molecular methods, I will be well-positioned to contribute to the advancement of the evolving field of GeroScience.

与年龄相关的身体机能下降很常见，并导致医疗保健费用增加、住院和 死亡。作为一名在骨骼肌衰老和身体功能方面拥有独特专业知识的传统流行病学家，我有 研究了生活方式干预措施（减肥、有氧运动和阻力训练），以防止与年龄相关的身体素质下降 功能。然而，生活方式的改变很难采取，特别是对于那些功能衰退风险最高的人来说。到 为了扩大这些干预措施的益处，必须了解功能变化背后的生物过程 随着衰老和后续干预。因此，当前的提案将为候选人提供高级培训 分子流行病学和衰老生物学，对身体功能的遗传和生物学基础产生新的见解 并为今后的研究奠定基础。特别是，目标 1 将识别基因和遗传变异 身体机能以及身体机能随衰老的变化。目标 2 将检查血液中 RNA 成分的表达 转化生长因子β（TGF-β）途径，该途径与肌肉功能障碍和致病性纤维化有关， 与身体机能及其随年龄的变化而变化。目标 3 将测试 TGF-β 和 3 型前胶原 N- 的血清水平是否 末端前肽（P3NP - 致病性纤维化的生物标志物）与老年人的身体功能相关。我会 利用可靠收集的身体功能测量、生物样本和超高密度全基因组 来自 NIA 资助的长寿家庭研究 (LLFS) 的多态性图谱，这是一项针对异常衰老和衰老的多中心研究 家庭的长寿和来自 基因组流行病学心脏与衰老研究队列 (CHARGE) 财团 。拟议的研究和培训非常有创新性。首先，尽管卷入了一些与年龄有关的事件 目前还没有人类研究检验 TGF-β 或 P3NP 与身体状况之间的关系 功能。此外，LLFS 有大量“高龄老人”，他们没有得到充分研究，且功能障碍风险最高。 衰退。关于身体机能遗传学的研究也很有限。拟议的职业发展奖 将为申请人提供人类遗传学和分子生物学方面重要的新指导、知识和技能 流行病学，包括但不限于血液 RNA 表达和蛋白质生物标志物开发（目标 2 和 3）， 全基因组关联 (GWA) 和连锁分析（目标 1 ），荟萃分析 （目标 1）和生物信息学（目标 1） 后续关联和连锁分析的方法。最后，这个奖项对于促进我的过渡至关重要 从事衰老和分子流行病学的独立研究生涯，重点关注身体功能。作为一个 具有传统和分子方法专业知识的流行病学家， 我将有能力为 不断发展的老年科学领域的进步。