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

与年龄相关的身体功能下降是常见的，并导致医疗费用增加，制度化和 死亡率。作为一名在骨骼肌衰老和身体机能方面拥有独特专业知识的传统流行病学家，我有 研究生活方式干预措施(减肥、有氧和阻力训练)以防止与年龄相关的体能下降 功能。然而，生活方式的改变很难接受，特别是对于那些功能衰退风险最高的人。至 要扩大这些干预措施的益处，就必须了解潜在的功能变化的生物学过程 随着年龄的增长和后续的干预。因此，目前的提议将为候选人提供以下方面的高级培训 衰老的分子流行病学和生物学，为身体机能的遗传和生物学基础提供了新的见解 并为今后的研究奠定了基础。特别是，AIM 1将识别基因和遗传变异 身体机能和身体机能随年龄增长的变化。AIM 2将检查血液RNA表达的成分 转化生长因子-β(转化生长因子-β)途径，与肌肉功能障碍和病理性纤维化有关。 与身体机能及其随年龄的变化有关。AIM 3将检测血清转化生长因子-β和3型前胶原N- 末端前肽(P3NP--一种病理性纤维化的生物标志物)与老年人的身体功能有关。这就做 利用强劲收集的身体机能测量、生物样本和超高密度全基因组 NIA资助的长寿家庭研究(LLFS)的多态图谱，这是一项关于异常衰老和 家庭和家庭中的长寿 基因组流行病学中心脏和衰老研究的队列(CHARE) 财团 。建议的研究和培训具有很强的创新性。首先，尽管与几起与年龄有关的案件有牵连 目前还没有研究表明转化生长因子-β或P3NP与生理状态之间的关系 功能。此外，LLFS有大量的“高龄老人”，他们的研究不足，功能性疾病的风险最高 拒绝。关于身体机能的遗传学研究也很有限。建议的职业发展奖 将为申请人提供基本的新的人类遗传学和分子方面的指导、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记物的发展(目标2和3)， 全基因组关联和连锁分析(目标1 )，元分析 (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，这个奖项将是促进我过渡的关键 致力于衰老和分子流行病学的独立研究，专注于身体机能。作为一种 在传统方法和分子方法方面都有专长的流行病学家， 我将处于有利地位，为 发展中的老年科学领域的进展。

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.