Genome Maintenance and Human Longevity -- AECM

基因组维护和人类长寿——AECM

• 批准号: 7943838
• 负责人: YOUSIN SUH
• 金额: $ 29.53万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-15 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7943838
• 关键词: Address; Affect; Age; Aging; Alleles; Apoptosis; Ashkenazim; Biochemical; Biological; Biological Markers; Candidate Disease Gene; Cell Aging; Cell Culture Techniques; Cells; Centenarian; Classification; Clinical; Code; Cohort Studies; Cultured Cells; DNA Repair; DNA Resequencing; Defect; Development; Disease; Elderly; Environmental Risk Factor; Family; Fibroblasts; Genes; Genetic; Genetic Variation; Genome; Genomic Instability; Genotype; Haplotypes; Health; Human; Individual; Inherited; Intervention; Lead; Longevity; Lymphocyte; Maintenance; Modeling; Molecular; Mus; Mutagens; Mutation; New England; Nucleotides; Pathway interactions; Phenotype; Population; Premature aging syndrome; Prevalence; Prevention therapy; Promoter Regions; Quality of life; Role; SNP genotyping; Screening procedure; Sequence Analysis; Serum; Severities; Staging; Structural Models; Testing; Translating; Untranslated Regions; Validation; Variant; age related; base; cellular engineering; cohort; fitness; follower of religion Jewish; genetic association; genetic variant; healthy aging; improved; in vivo; insight; interdisciplinary approach; mouse model; novel; novel strategies; offspring; prevent; programs; response; trait

The main objective of this project is to test the hypothesis that polymorphic variation at loci involved in genome maintenance relates to the onset and severity of aging phenotypes in humans and, possibly, to aging rate in general. To address this hypothesis, we propose an approach to discover genetic variants involved in genome maintenance pathways that are either enriched (beneficial alleles) or depleted (deleterious alleles) in families with exceptional longevity. For this purpose, we plan to identify functional SNP haplotypes (comprehensive candidate gene approach) of -100 genes in 5 genome maintenance pathways for association analysis with aging-related phenotypes, including exceptionally healthy aging, in individuals of an ongoing Ashkenazi Jewish Centenarian Study Cohort. The candidate genes include all genes in which heritable mutations have been found associated with accelerated aging in mice as well as genes interacting with these "key genes" and other genes acting in the same pathway. To ascertain the functional relevance of observed positive associations, candidate gene-SNP haplotypes will be modeled in cells and screened for various parameters of cellular fitness in short term cell culture studies to provide insight into their biological significance. Functionally relevant gene variants can then be further studied for their in vivo effect during aging by modeling them in the mouse. The results are expected to provide the first evidence that variants of the same genes found to give rise to premature aging phenotypes in the mouse are actually segregating in human populations with aging-related phenotypes and life span. This will help to translate the results obtained in the program project into targeted and personalized intervention strategies, ultimately leading to improved quality of life of the elderly population.

该项目的主要目标是检验以下假设：涉及基因座的多态性变异 基因组维护与人类衰老表型的发生和严重程度有关，并且可能与 老化率一般。为了解决这个假设，我们提出了一种发现遗传变异的方法 参与富集（有益等位基因）或耗尽的基因组维护途径 （有害等位基因）存在于特别长寿的家庭中。为此，我们计划确定功能 5个基因组维护中-100个基因的SNP单倍型（综合候选基因方法） 与衰老相关表型（包括异常健康的衰老）进行关联分析的途径 正在进行的德系犹太人百岁老人研究队列的个体。候选基因包括所有 已发现与小鼠加速衰老相关的遗传突变基因 与这些“关键基因”以及在同一途径中起作用的其他基因相互作用的基因。为了确定 观察到的正关联的功能相关性，候选基因 SNP 单倍型将在以下模型中建模 细胞并在短期细胞培养研究中筛选细胞适应性的各种参数，以提供 深入了解它们的生物学意义。然后可以进一步研究功能相关的基因变体 通过在小鼠中模拟它们在衰老过程中的体内作用。结果预计将提供第一个 有证据表明，相同基因的变体会导致小鼠过早衰老的表型 实际上在具有与衰老相关的表型和寿命的人群中是分离的。这将有助于 将计划项目中获得的结果转化为有针对性的个性化干预策略， 最终提高老年人的生活质量。