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

• 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
• 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

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、糖尿病和糖尿病。 疾病、癌症和神经变性。在建议的U19合作提案中，我们将测试一种新的 开发治疗这些疾病的方法。与其关注个别疾病， 探索成功老龄化，健康的百岁老人和对照个体之间的遗传差异， 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寿命和健康跨度有关的基因座，如蠕虫和 小鼠利用阿尔伯特·爱因斯坦医学院的百岁老人资源，我们将鉴定出罕见的遗传病。 与健康长寿的保守机制相关的变异体和microRNA作为潜在的靶点， 药物发现（项目1），在小鼠模型中评估这些变体或相关途径的功能， 衰老，包括自然衰老，与晚年人类健康相关的表型（项目2），以及随后的 利用它们作为开发和测试小分子的先导，这些小分子靶向受这些罕见的 变体和miRNAs（项目3）。这个综合研究项目将得到两个核心的支持： 管理核心协调研究（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公司的 合作伙伴Regeneron，我们还将进一步确认和验证一些遗传变异， 此外，新的遗传变异和相关途径对人类长寿很重要。拟议 该项目将大大增加我们对保守的促长寿途径重要性的理解， 目前为止，大多数研究都是在模型生物中进行的，用于人类衰老。重要的是，这种基因对药物 一个合作项目将是第一个使用健康老龄化的罕见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有关的疾病。