Identification and characterization of functional genetic variants associated with human longevity

与人类长寿相关的功能性遗传变异的鉴定和表征

基本信息

批准号：
10714392
负责人：
JAN VIJG
金额：
$ 61.32万
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：
2017
资助国家：
美国
起止时间：
2017-09-15 至 2028-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10714392
关键词：
Age-associated memory impairment Aging Alzheimer&apos s Disease Alzheimer&apos s disease risk Attenuated Biochemical Biological Biological Assay Cardiovascular Diseases Cell Aging Cell model Cellular Assay Centenarian Chronic Disease Clustered Regularly Interspaced Short Palindromic Repeats Code Cognitive Collaborations Data Disease Drug Targeting FRAP1 gene Frequencies Gene Expression Genes Genetic Genomics Genotype Goals Health Human Human Engineering Human Genetics Insulin Insulin-Like Growth Factor I Intervention Laboratories Longevity Longevity Pathway MADH3 gene Malignant Neoplasms Methods Molecular NFKBIA gene Nematoda Neurodegenerative Disorders Pathology Pathway interactions Phenotype Primates Process Proteins Reporter Research Personnel Resistance Risk Risk Factors Rodent Role Severities Signal Pathway Signal Transduction Stress Testing Therapeutic Translating Untranslated RNA Validation Variant Yeasts age related causal variant cell type dietary drug discovery economic cost epigenomics exome sequencing experimental study fly follower of religion Jewish frailty genetic variant genome wide association study healthspan healthy aging high throughput screening human genomics human pluripotent stem cell human tissue improved interdisciplinary approach model organism multiple omics new therapeutic target novel novel therapeutics pharmacologic protein expression protein function resilience screening social therapeutic target

项目摘要

Abstract Recent advances in human genetics and genomics provide novel opportunities for the identification and validation of drug targets. Studies in model organisms have demonstrated that the rate of aging and the frequency and severity of age-related pathologies are influenced by conserved genetic pathways and factors which, when targeted genetically, pharmacologically, or through dietary modulation, can extend lifespan and healthspan. This overwhelming evidence raises hopes for new drugs that slow the aging process and attenuate age-related disease in humans by modulating these conserved pathways of aging. In Project 2 (old Project 1), we have been conducting the experiments aimed at exactly this goal: To identify and functionally characterize genetic variants in the conserved pathways of aging that are associated with human healthy aging and extreme longevity for therapeutic modulation to improve human healthspan and lifespan. We demonstrated through cell models that longevity-associated rare coding variants in SIRT6, USP35, and UBE3C alter protein function and/or expression which antagonize age-related deleterious changes in human tissues and during cellular senescence. We found the same aging-antagonizing effects of longevity-associated non-coding variants in SMAD3 and the 3 genes (NFKBIA, CLU and PRKCH) involved in the PKC/NF-B signaling pathways. In the renewal application, Project 2 proposes to confirm and extend our observations by taking a systematic multidisciplinary approach. The objective of Project 2 is to identify and directly test the impact of causal variants, whose genetic perturbations underlie the association with longevity. Our approach is to use high-throughput screening methods, such as INtegrated PrOtein INteractome perTurbation screening (InPOINT) for coding variants and Massively Parallel Reporter Assay (MPRA) for non-coding variants, and to investigate the underlying mechanisms using CRISPR- engineered human pluripotent stem cells (hPSC), multiple cellular differentiation paradigms, multiomics approaches, and functional analysis composed of molecular, biochemical, and cellular assays. Our functional analyses of longevity-associated variants in SIRT6, USP35, and UBE3C point to their potential role in protection against age-related cognitive decline and risk of Alzheimer’s disease (AD) and on the phenotypes of cellular senescence, which are increasingly implicated in neurodegenerative disease. Thus, we will focus on the aging- antagonizing effects of the SIRT6, UBE3C, and USP35 coding variants in the context of cognitive health and protection from AD. The ultimate impact of Project 2 lies in its potential to reveal conserved pathways as fundamental mechanisms of aging in humans and as therapeutic targets for healthy aging, in close collaboration with Projects 1, 3, 4 and Core B.

抽象的人类遗传学和基因组学的最新进展为识别和基因组学提供了新的机会。药物靶标的验证。对模型生物体的研究表明，衰老速度和与年龄相关的病理的频率和严重程度受到保守的遗传途径和因素的影响当通过基因、药理学或饮食调节进行靶向治疗时，可以延长寿命并这一压倒性的证据给人们带来了对减缓衰老过程和减弱新药的希望。在项目 2（旧项目 1）中，通过调节这些保守的衰老途径来治疗人类的年龄相关疾病。我们一直在进行实验，正是为了这个目标：识别和功能表征与人类健康衰老和极端衰老相关的保守衰老途径中的遗传变异我们通过细胞证明了治疗调节的长寿性，可以改善人类的健康和寿命。 SIRT6、USP35 和 UBE3C 中与长寿相关的罕见编码变异改变蛋白质功能的模型和/或拮抗人体组织和细胞衰老过程中与年龄相关的有害变化的表达。我们发现 SMAD3 和 3 中与长寿相关的非编码变体具有相同的抗衰老作用。参与 PKC/NF-κB 信号通路的基因（NFKBIA、CLU 和 PRKCH）在更新应用中，项目 2 建议通过采取系统的多学科方法来确认和扩展我们的观察结果。项目 2 的目标是识别并直接测试因果变异的影响，其遗传扰动我们的方法是使用高通量筛选方法，例如用于编码变体和大规模并行的集成蛋白质相互作用组微扰筛选 (InPOINT) 针对非编码变异的报告基因检测 (MPRA)，并使用 CRISPR 研究潜在机制工程人类多能干细胞 (hPSC)、多种细胞分化范式、多组学我们的功能分析包括分子、生化和细胞分析。对 SIRT6、USP35 和 UBE3C 中与长寿相关的变异的分析表明它们在保护方面的潜在作用对抗与年龄相关的认知能力下降和阿尔茨海默氏病 (AD) 的风险以及细胞表型衰老与神经退行性疾病的关系越来越密切，因此，我们将重点关注衰老。 SIRT6、UBE3C 和 USP35 编码变体在认知健康和认知健康方面的拮抗作用项目 2 的最终影响在于其揭示保守途径的潜力人类衰老的基本机制和健康衰老的治疗目标，密切合作包含项目 1、3、4 和核心 B。