Genetic Determinants of Human Transcriptional Aging

描述（由申请方提供）：在从分子途径到器官系统的所有组织水平上均观察到人类的年龄效应。虽然有大量证据表明遗传变异影响衰老发生的速度，但识别参与人类差异衰老的特定基因一直很困难。大多数关于衰老的人类遗传学研究都集中在异常长寿上，这可能与基因的直接作用相距太远，而不是遗传解剖的可靠表型。此外，公众对老龄化的关注主要集中在维持老年人的正常功能，而不是绝对寿命。在拟议的项目中，我们专注于特定分子通路中的定量差异衰老，这应该提供一种更强大的方法来识别参与衰老过程中人类变异的特定基因及其序列变体。在这个项目中，我们将使用大规模的淋巴细胞全基因组转录谱来鉴定一组新的基于基因表达的生物标志物，以鉴定参与差异老化的定量表型。这种表型具有直接接近基因作用的巨大优势。现有的主要人类遗传资源（来自圣安东尼奥家族心脏研究的家族）将被用于以具有成本效益的方式检查转录衰老的遗传基础。将使用来自1，240名墨西哥裔美国人的广泛的全基因组基因型和转录组数据，这些墨西哥裔美国人是大型扩展谱系的成员。对淋巴细胞样本现有的横截面转录谱的分析显示，超过4,000个与年龄相关的定量转录本。在这个项目中，我们将使用初始基线检查后15年获得的淋巴细胞对其中1,000名个体进行后续转录谱分析。使用这些新的混合纵向转录数据，我们将确定基因和它们的序列变异，影响差异老化。该项目的具体目标是：（1）从1，000名墨西哥裔美国人中开发一个淋巴细胞全基因组转录谱的混合纵向样本，这些人是大型扩展激酶的成员;（2）定位影响功能/途径特异性生物年龄的数量性状基因座，以便使用基于连锁的基因组扫描检测差异衰老的遗传调节因子;和（3）鉴定与年龄相互作用的特异性调节变体，以影响六十个新的顺式调节衰老相关基因的转录水平。这项拟议中的研究将导致发现人类生物衰老变异的新基因。通过关注新的表达为基础的表型显示出与年龄相关的顺式调节，我们将最大限度地提高我们的概率，找到影响差异老化的因果遗传变异。由于老龄化造成的死亡目前每年花费美国数十亿美元，并且这种经济负担正在迅速增加。在这个项目中，我们将确定参与人类对衰老的差异反应的基因。更好地了解分子衰老的遗传基础，将提供新的方法来表征，治疗和潜在的预防衰老过程中的活力丧失，并可能导致显着减少这一相当大的公共卫生负担。

DESCRIPTION (provided by applicant): Age effects in humans are observed at all levels of organization from molecular pathways to organ systems. While there is substantial evidence that genetic variation influences the rate at which aging occurs, identifying the specific genes involved in human differential aging has been difficult. Most human genetic studies of aging have focused on exceptional longevity which may be too far removed from the direct action of genes to be a reliable phenotype for genetic dissection. Additionally, much of the public health interest in aging is less in absolute longevity than in maintenance of normal function in old age. In the proposed project, we focus on quantitative differential aging in specific molecular pathways which should offer a more powerful approach to identify specific genes and their sequence variants that are involved in human variation in the aging process. In this project, we will identify a novel set of gene expression-based biomarkers using large-scale genome- wide transcriptional profiling of lymphocytes to identify quantitative phenotypes that are involved in differential aging. Such phenotypes have the great advantage of being directly proximal to gene action. An existing major human genetic resource (families from the San Antonio Family Heart Study) will be employed to examine the genetic basis of transcriptional aging in a cost-effective way. Extensive genome-wide genotypic and transcriptomic data from 1,240 Mexican Americans who are members of large extended pedigrees will be used. Analysis of existing cross-sectional transcriptional profiles from lymphocyte samples have revealed over 4,000 quantitative transcripts that correlate with age. For this project, we will perform follow-up transcriptional profiles on 1,000 of these individuals using lymphocytes obtained 15 years after the initial baseline examination. Using these novel mixed longitudinal transcriptional data, we will identify genes and their sequence variants that influence differential aging. The specific aims of this project are to: (1) develop a mixed longitudinal sample of genome-wide transcriptional profiles of lymphocytes from 1,000 Mexican Americans who are members of large extended kindreds; (2) localize quantitative trait loci influencing function/pathway-specific biological ages in order to detect genetic regulators of differential aging using linkage-based genome scanning; and (3) identify specific regulatory variants that interact with age to influence transcript levels in sixty novel cis-regulated aging-related genes. The proposed research should lead to the discovery of novel genes underlying variation in human biological aging. By focusing on novel-expression based phenotypes shown to be both age-related cis-regulated, we will maximize our probability for finding causal genetic variants influencing differential aging. Morbidity due to aging currently costs the United States billions of dollars annually and this economic burden is rapidly increasing. In this project, we will identify genes involved in human differential response to aging. A better understanding of the genetic underpinnings of molecular aging will provide novel approaches for the characterization, treatment and potential prevention of loss of vitality during aging and may lead to a significant reduction of this considerable public health burden.