Genetic Determinants of Human Transcriptional Aging

人类转录衰老的遗传决定因素

• 批准号: 8026871
• 负责人: SARAH A. WILLIAMS-BLANGERO
• 金额: $ 54.16万
• 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/8026871
• 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各个组织中观察到人类的年龄效应。尽管有大量证据表明遗传变异会影响衰老的发生率，但很难识别与人类差异衰老有关的特定基因。大多数人类衰老的遗传研究都集中在特殊的寿命上，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，与老年人的正常功能相比，大部分公共健康兴趣的绝对寿命少。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，该途径应该提供更强大的方法来识别特定基因及其序列变体，这些序列及其序列变体涉及衰老过程中人类变异。在这个项目中，我们将使用大规模基因组的淋巴细胞转录分析确定一组新型的基于基因表达的生物标志物，以鉴定与差异衰老相关的定量表型。这种表型具有直接靠近基因作用的很大优势。将采用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族）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基因组基因型和转录组数据，这些数据将使用大型扩展血统的成员。对淋巴细胞样品的现有横截面转录谱的分析显示，已有4,000多种与年龄相关的定量转录本。对于该项目，我们将使用初始基线检查15年获得的淋巴细胞对1,000名个人进行后续转录概况。使用这些新型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体。该项目的具体目的是：（1）从1000名墨西哥裔美国人的淋巴细胞的全基因组转录特征的混合纵向样本中，这些淋巴细胞是大型扩展金的成员； （2）定位定量性状基因座影响功能/途径特异性生物年龄，以便使用基于链接的基因组扫描来检测差异衰老的遗传调节剂； （3）确定与年龄相互作用的特定调节变体，以影响60个新型CIS调节的与衰老相关的基因的转录水平。拟议的研究应导致发现人类生物衰老的新基因。通过专注于与年龄相关的顺式调节的新型基于表达的表型，我们将最大程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，由于老化而导致的发病率每年损失美国数十亿美元，这种经济负担正在迅速增加。在这个项目中，我们将确定涉及人类差异反应的基因。更好地了解分子衰老的遗传基础，将为衰老期间的表征，治疗和潜在预防活力丧失提供新的方法，并可能导致这种大量公共卫生负担大大减轻。