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，癌症和神经退行性。在拟议的协作U19提案中，我们将测试一个新的开发这些疾病疗法的方法。而不是专注于个体疾病，我们将探索成功老化的，健康的百岁老人和对照没有的人之间的遗传差异极端长寿的家族史。基于我们自己的初步结果，许多此类遗传差异影响基因座已知与模型生物（例如蠕虫和蠕虫生物）的寿命和健康跨度有关的基因座老鼠。利用阿尔伯特·爱因斯坦医学院的百年纪念资源，我们将确定罕见的遗传与健康寿命作为潜在目标的保守机制相关的变体和microRNA，用于药物发现（项目1），在小鼠模型中评估这些变体或相关途径与晚期人类健康相关的表型的衰老，包括自然衰老（项目2），随后将它们用作开发和测试针对受这些罕见途径的小分子的引线变体和miRNA（项目3）。这个集成的研究项目将得到两个核心的支持：协调研究（核心A）和基因工程鼠标的行政核心和老年病理学核心（核心B）。使用我们的广泛遗传资源，包括我们的药物合作伙伴Regeneron，我们还将进一步确认并验证一些遗传变异并发现其他新型的遗传变异和相关途径对于人类寿命很重要。提议项目应大大提高我们对保守亲态途径的重要性的理解，在模型生物体中识别并主要研究人类衰老。重要的是，该药物的基因协作项目将是第一个使用健康衰老的稀有人物的遗传学作为指南开发用于靶向衰老的治疗方法，而不是其复合疾病防止，延迟发作和进展，甚至可能恢复许多与年龄有关的疾病。