Genetic Determinants of Human Transcriptional Aging

描述(由申请人提供)：从分子途径到器官系统的所有组织水平都观察到了人类的年龄效应。虽然有大量证据表明，遗传变异会影响衰老的发生速度，但识别与人类差异衰老有关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，这种长寿可能离基因的直接作用太远，不能成为基因解剖的可靠表型。此外，公众对衰老的大部分健康兴趣与其说是绝对长寿，不如说是在老年时维持正常的功能。在拟议的项目中，我们专注于特定分子途径中的定量差异衰老，这将提供一种更强大的方法来识别与人类衰老过程中的变异有关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全基因组转录图谱来识别一组新的基于基因表达的生物标记物，以识别与差异衰老有关的定量表型。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(来自圣安东尼奥家庭心脏研究的家庭)将被用来以具有成本效益的方式研究转录衰老的遗传基础。将使用来自1240名墨西哥裔美国人的广泛的全基因组基因分型和转录组数据，这些美国人是大型扩展家系的成员。对淋巴细胞样本现有的横截面转录图谱的分析表明，超过4,000个定量转录与年龄有关。在这个项目中，我们将使用最初基线检查15年后获得的淋巴细胞对其中1,000人进行后续转录分析。使用这些新的混合纵向转录数据，我们将识别影响差异衰老的基因及其序列变体。该项目的具体目标是：(1)开发来自1,000名墨西哥裔美国人(他们是大家族成员)全基因组转录谱的混合纵向样本；(2)定位影响功能/途径特定生物年龄的数量性状基因座，以便利用基于连锁的基因组扫描来检测差异衰老的遗传调节因子；以及(3)识别与AGE相互作用的特定调控变异体，以影响60个新的顺式调节的衰老相关基因的转录水平。这项拟议的研究应该会导致发现人类生物衰老中潜在变异的新基因。通过专注于基于新表达的表型，我们将最大限度地发现影响差异衰老的因果遗传变异。由于老龄化导致的发病率目前每年给美国造成数十亿美元的损失，而且这一经济负担正在迅速增加。在这个项目中，我们将识别与人类对衰老的差异反应有关的基因。更好地了解分子衰老的遗传基础将为表征、治疗和潜在地预防衰老过程中的活力丧失提供新的方法，并可能导致这一相当大的公共卫生负担的显著减轻。

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.