Genetic Determinants of Human Transcriptional Aging

人类转录衰老的遗传决定因素

• 批准号: 7354276
• 负责人: SARAH A. WILLIAMS-BLANGERO
• 金额: $ 53.67万
• 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 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7354276
• 关键词: Adult; Age; Aging; Aging-Related Process; Biological Aging; Biological Markers; Biological Process; Candidate Disease Gene; Cardiovascular system; Complex; DNA; DNA Resequencing; Data; Detection; Development; Dissection; Economic Burden; Environmental Exposure; Exhibits; Extended Family; Family; Gene Expression; Genes; Genetic; Genetic Determinism; Genetic Variation; Genetic screening method; Genome; Genome Scan; Genotype; Heart; Human; Human Genetics; Individual; Lead; Localized; Longevity; Lymphocyte; Maintenance; Mammals; Measures; Mental Health; Methods; Mexican Americans; Modeling; Molecular; Morbidity - disease rate; Nucleotides; Pathway interactions; Phenotype; Physiological; Prevention; Probability; Procedures; Promoter Regions; Public Health; Quantitative Genetics; Quantitative Trait Loci; Rate; Research; Resources; Role; Sampling; Sampling Studies; Testing; Transcript; United States; Variant; age effect; age related; base; body system; cost; follow-up; genetic linkage analysis; genetic pedigree; genetic resource; genetic variant; indexing; interest; kindred; member; novel; novel strategies; programs; promoter; 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各个组织层面都可以观察到年龄对人类的影响。虽然有大量证据表明遗传变异会影响衰老发生的速度，但识别与人类差异性衰老有关的特定基因一直很困难。大多数人类衰老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，无法成为遗传解剖的可靠表型。此外，公众健康对老龄化的兴趣大多不是对绝对寿命的关注，而是对老年时正常功能的维持。在拟议的项目中，我们重点关注特定分子途径中的定量差异衰老，这应该提供更强大的方法来识别与衰老过程中人类变异有关的特定基因及其序列变异。在这个项目中，我们将利用淋巴细胞的大规模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，以鉴定参与差异性衰老的定量表型。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数据，这些墨西哥裔美国人属于大型扩展谱系的成员。对淋巴细胞样本现有横断面转录谱的分析揭示了超过 4,000 个与年龄相关的定量转录本。对于这个项目，我们将使用初始基线检查 15 年后获得的淋巴细胞对其中 1,000 名个体进行后续转录谱分析。利用这些新颖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异。该项目的具体目标是：(1) 开发来自 1,000 名墨西哥裔美国人（大家族成员）的淋巴细胞全基因组转录谱的混合纵向样本； (2) 定位影响功能/途径特异性生物年龄的数量性状位点，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； (3) 鉴定与年龄相互作用以影响 60 个新的顺式调控衰老相关基因的转录水平的特定调控变异。拟议的研究应该会导致人类生物衰老变异背后的新基因的发现。通过关注与年龄相关的顺式调节的基于新颖表达的表型，我们将最大限度地找到影响差异衰老的因果遗传变异的可能性。目前，老龄化导致的发病率每年给美国造成数十亿美元的损失，而且这种经济负担正在迅速增加。在这个项目中，我们将鉴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，并可能显着减轻这一巨大的公共健康负担。