Genetic Determinants of Human Transcriptional Aging

人类转录衰老的遗传决定因素

• 批准号: 8220802
• 负责人: SARAH A. WILLIAMS-BLANGERO
• 金额: $ 55.67万
• 依托单位: TEXAS BIOMEDICAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-02-15 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8220802
• 关键词: Adult; Age; Aging; Aging-Related Process; Biological Aging; Biological Markers; Biological Process; Cardiovascular system; Complex; Data; Detection; Development; Dissection; Economic Burden; Environmental Exposure; Extended Family; Family; Gene Expression; Genes; Genetic; Genetic Determinism; Genetic Variation; Genome Scan; Genotype; Heart; Human; Human Genetics; Individual; Lead; Longevity; Lymphocyte; Maintenance; Mammals; Measures; Mental Health; Methods; Mexican Americans; Modeling; Molecular; Morbidity - disease rate; Names; Pathway interactions; Phenotype; Physiological; Prevention; Principal Investigator; Probability; Procedures; Public Health; Quantitative Trait Loci; Research; Resources; Role; Sampling; Sampling Studies; Transcript; United States; Variant; age effect; age related; base; body system; cost; cost effective; follow-up; genetic pedigree; genetic resource; genetic variant; genome-wide; indexing; interest; kindred; longitudinal analysis; member; novel; novel strategies; programs; response; trait; transcriptomics

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.

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，但确定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研究都集中在异常长寿上，这可能与基因的直接作用相距甚远，无法作为遗传解剖的可靠表型。此外，公众对老龄化的兴趣更多的是在老年时维持正常功能，而不是绝对长寿。在拟议的项目中，我们将重点研究特定分子途径中的定量差异衰老，这将为识别人类衰老过程中涉及的特定基因及其序列变异提供更有力的方法。在这个项目中，我们将鉴定一组新的基于基因表达的生物标志物，使用大规模的全基因组淋巴细胞转录谱来鉴定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）将被用于以经济有效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全基因组基因型和转录组学数据，这些人是大型扩展谱系的成员。现有淋巴细胞样本的横断面转录谱分析揭示了超过4000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1000名这些个体进行随访转录谱分析。利用这些新的混合纵向转录数据，我们将确定影响差异衰老的基因及其序列变异。该项目的具体目标是：(1)开发来自1000名墨西哥裔美国人的淋巴细胞全基因组转录谱的混合纵向样本，这些人都是大扩展家族的成员；(2)定位影响功能/途径特异性生物年龄的数量性状位点，利用基于连锁的基因组扫描检测差异衰老的遗传调控因子；(3)确定与年龄相互作用的特定调控变异，从而影响60个新型顺式调控的衰老相关基因的转录水平。拟议的研究应该导致发现新的基因在人类生物衰老的变化。通过关注与年龄相关的顺式调节的基于新表达的表型，我们将最大限度地提高发现影响差异衰老的因果遗传变异的可能性。目前，美国每年因老龄化引起的疾病花费数十亿美元，而且这一经济负担正在迅速增加。在这个项目中，我们将确定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衰老过程中活力丧失的表征、治疗和潜在预防提供新方法，并可能显著减少这一相当大的公共卫生负担。