Genetic variant-based drug discovery targeting conserved pathways of aging

针对保守的衰老途径的基于遗传变异的药物发现

基本信息

批准号：
9916672
负责人：
JAN VIJG
金额：
$ 187.65万
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 2022-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9916672
关键词：
Affect Aging Animal Model Apoptosis Biological Assay Cardiovascular Diseases Cell Aging Cell Culture System Cells Centenarian Clinical Code Collaborations Development Disease Drug Targeting Elderly FDA approved FRAP1 gene FVB Mouse Family history of Foundations Gene Expression Genes Genetic Genetic Variation Genetically Engineered Mouse Genome engineering Genomic Instability Genotype Health Human Human Engineering Human Genetics Hybrids I Kappa B-Alpha IGF1 gene Individual Intervention Link Longevity Longevity Pathway Malignant Neoplasms Medicine MicroRNAs Modeling Molecular Mus Mutagens Natural Products Nature Nerve Degeneration Non-Insulin-Dependent Diabetes Mellitus Nucleic Acid Regulatory Sequences Outcome Pathologic Pathway interactions Pharmaceutical Preparations Pharmacologic Substance Pharmacology Phenotype Physiological Processes Plague Population Regulation Research Research Project Grants Resources Risk Factors Signal Transduction Symptoms Testing Therapeutic Untranslated RNA Variant age related aged base college drug discovery efficacy testing exome experimental study follower of religion Jewish genetic resource genetic variant healthspan healthy aging human disease in silico middle age mouse model mutant novel novel strategies novel therapeutics prevent rare variant response screening small molecule small molecule inhibitor therapeutic development therapy development tool ward whole genome

项目摘要

ABSTRACT - OVERALL Aging is an important risk factor for most common human diseases, including type 2 diabetes, cardiovascular disease, cancer and neurodegeneration. In the proposed collaborative U19 proposal, we will test a new approach for developing therapies for these diseases. Rather than focusing on individual diseases, we will explore genetic differences between successfully aged, healthy centenarians and control individuals with no family history of extreme longevity. Based on our own preliminary results, many of such genetic differences affect loci known to be involved in extreme longevity and health span in model organisms, such as worms and mice. Using the centenarian resource at the Albert Einstein College of Medicine, we will identify rare genetic variants and microRNAs associated with conserved mechanisms of healthy longevity as potential targets, for drug discovery (Project 1), evaluate these variants or associated pathways functionally in mouse models of aging, including natural aging, for phenotypes relevant for late-life human health (Project 2), and subsequently use them as leads for developing and testing small molecules targeting the pathways affected by these rare variants and miRNAs (Project 3). This integrated research project will be supported by two cores: an Administrative Core to coordinate the research (Core A) and a Genetically Engineered Mouse and Geropathology Core (Core B). Using our extensive genetic resources, including some from our pharmaceutical partner, Regeneron, we also will confirm further and validate some of the genetic variants and discover additional, novel genetic variants and associated pathways important for human longevity. The proposed project should greatly increase our understanding of the importance of the conserved pro-longevity pathways, identified and thus far mostly studied in model organisms, for human aging. Importantly, this gene to drugs collaborative project will be the first to use the genetics of rare individuals with healthy aging as a guide for the development of therapeutic approaches for targeting aging itself rather than its composite diseases for preventing, delaying onset and progression, and possibly even reverting many multiple age-related diseases.

摘要 - 总体衰老是大多数常见人类疾病的重要危险因素，包括2型糖尿病、心血管疾病疾病、癌症和神经退行性疾病。在拟议的 U19 协作提案中，我们将测试一个新的开发针对这些疾病的疗法的方法。我们不会关注个别疾病，探索成功老龄化、健康的百岁老人和没有健康状况的对照个体之间的遗传差异极其长寿的家族史。根据我们自己的初步结果，许多此类遗传差异影响已知与模式生物的极端长寿和健康跨度有关的位点，例如蠕虫和老鼠。利用阿尔伯特·爱因斯坦医学院的百岁老人资源，我们将鉴定罕见的遗传基因与健康长寿的保守机制相关的变异和 microRNA 作为潜在目标药物发现（项目 1），在小鼠模型中功能性地评估这些变异或相关通路衰老，包括自然衰老，针对与晚年人类健康相关的表型（项目 2），以及随后使用它们作为开发和测试针对受这些罕见疾病影响的途径的小分子的先导变体和 miRNA（项目 3）。该综合研究项目将得到两个核心的支持：协调研究的行政核心（核心 A）和基因工程小鼠老年病理学核心（核心 B）。利用我们广泛的遗传资源，包括一些来自我们制药的遗传资源合作伙伴Regeneron，我们也会进一步确认和验证一些基因变异并发现此外，新的遗传变异和相关途径对人类长寿很重要。拟议的该项目应该大大增加我们对保守的长寿途径重要性的理解，迄今为止，主要是在模型生物体中对人类衰老进行了鉴定和研究。重要的是，这个基因对药物该合作项目将是第一个利用健康衰老的稀有个体的遗传学作为指导的项目开发针对衰老本身而不是其复合疾病的治疗方法预防、延缓发病和进展，甚至可能逆转许多多种与年龄相关的疾病。