Genome maintenance and human longevity

基因组维护和人类长寿

基本信息

批准号：
8742955
负责人：
YOUSIN SUH
金额：
$ 51.86万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-30 至 2019-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8742955
关键词：
Age Aging Apoptosis Ashkenazim B-Lymphocytes Biological Preservation Cell Aging Cell Culture System Cell Culture Techniques Cell Death Cells Centenarian Collaborations Computer Simulation DNA Damage DNA Double Strand Break DNA Repair DNA Resequencing Defect Development Disease Epigenetic Process Gene Expression Genes Genetic Genetic Predisposition to Disease Genome Genome engineering Genomic Instability Genotype Health Human IGF1 gene Intervention Longevity Maintenance MicroRNAs Modeling Molecular Mus Mutagens Mutation Outcome Pathway interactions Phenotype Plasma Premature aging syndrome Prevention therapy Regulator Genes Repression Research Signal Transduction Testing Translating Validation Variant age related base cohort fitness follower of religion Jewish genetic variant healthy aging human FRAP1 protein in vivo interdisciplinary approach interest mouse model novel strategies prevent programs protein expression rare variant repaired response tool validation studies

项目摘要

ABSTRACT (PROJECT 4) Evidence from this program project (PPG) demonstrated that defects in genome maintenance cause premature aging in mice. The contribution of genome maintenance to human longevity, however, remains to be established. The main objective of Project 4 (Previous Project 5) has been to translate the PPG's breakthrough discoveries into the human situation by testing the hypothesis that polymorphic variation at loci involved in genome maintenance relates to longevity and healthy aging phenotypes in humans. Research in Project 4 has led to the discovery of genetic and epigenetic signatures associated with human longevity: (1) enrichment of rare variants predicted to change the function and/or expression of proteins involved in signaling and repair of DNA double strand breaks (DSBs) in centenarians as compared to controls; and (2) upregulated microRNAs (miRNAs) in both immortalized B-cells and plasma of centenarians as compared to controls. Interestingly, some of these miRNAs were found, by Project 1, to induce cell preservation responses and cell death repression in the presence of unrepaired DNA damage. We hypothesize that a cluster of protective (epi)genotypes in the genome maintenance gene regulatory network is necessary to achieve exceptional longevity in humans. To confirm and extend our observations that support this hypothesis, we propose a systematic multidisciplinary approach to validate the longevity-associated (epi)genotype signatures and investigate the underlying molecular mechanisms to ascertain the functional relevance of observed positive associations by testing various parameters of cellular fitness in short-term cell culture studies in collaboration with all other Projects. Functionally relevant gene variants and miRNAs will then be further studied for their in vivo effect during aging by modeling them in the mouse in collaboration with Core B. The information generated in Project 4 will provide a mechanistic understanding of the causal relationships between genotypes, miRNA expression, and the associated phenotypes, potentially leading to interventions that promote survival and health in people without genetic predisposition to exceptional longevity.

摘要（项目 4）该计划项目 (PPG) 的证据表明，基因组维护缺陷会导致小鼠过早衰老。然而，基因组维护对人类长寿的贡献仍有待研究。已确立的。项目 4（之前的项目 5）的主要目标是转化 PPG 的突破通过测试涉及基因座的多态性变异的假设，对人类状况进行了发现基因组维护与人类的长寿和健康衰老表型有关。项目4的研究有导致发现与人类长寿相关的遗传和表观遗传特征：（1）罕见变异预计会改变参与信号传导和修复的蛋白质的功能和/或表达与对照组相比，百岁老人的 DNA 双链断裂 (DSB)； (2) 上调的 microRNA 与对照相比，百岁老人永生化 B 细胞和血浆中的 (miRNA)。有趣的是，项目 1 发现其中一些 miRNA 可诱导细胞保存反应和细胞死亡存在未修复的 DNA 损伤时的抑制。我们假设有一组保护性的基因组维护基因调控网络中的（epi）基因型对于实现卓越的效果是必要的人类的长寿。为了证实并扩展我们支持这一假设的观察结果，我们提出了系统的多学科方法来验证与长寿相关的（epi）基因型特征和研究潜在的分子机制，以确定观察到的阳性结果的功能相关性通过在短期细胞培养研究中合作测试细胞适应性的各种参数来建立关联与所有其他项目。然后将进一步研究功能相关的基因变体和 miRNA，以了解它们的作用与 Core B 合作，通过在小鼠体内模拟它们在衰老过程中的体内效应。项目 4 中生成的结果将提供对基因型之间因果关系的机械理解， miRNA 表达和相关表型，可能导致促进生存的干预措施和没有长寿遗传倾向的人的健康。