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: 9359668
• 负责人: JAN VIJG
• 金额: $ 191.07万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE, INC
• 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/9359668
• 关键词: Affect; Aging; Animal Model; Apoptosis; Biological Assay; Cardiovascular Diseases; Cell Aging; Cell Culture System; Cells; Centenarian; Clinical; Code; Collaborations; Computer Simulation; Development; Disease; Drug Targeting; Elderly; FDA approved; FRAP1 gene; FVB Mouse; Family history of; Foundations; Gene Expression; Gene Targeting; 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; healthy aging; human disease; 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 衰老是人类大多数常见疾病的重要风险因素，包括2型糖尿病、心血管疾病 疾病、癌症和神经退化。在提议的协作U19提案中，我们将测试一个新的 为这些疾病开发治疗方法的方法。与其专注于个别疾病，我们将 探讨健康百岁老人与健康百岁老人之间的遗传差异 极长寿的家族病史。根据我们自己的初步结果，许多这样的遗传差异 影响模式生物中已知与极端长寿和健康持续时间有关的基因座，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，我们将识别罕见的基因 与健康长寿的保守机制相关的变体和microRNA作为潜在的靶标， 药物发现(项目1)，在小鼠模型中评估这些变异或相关途径的功能 老龄化，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 将它们用作开发和测试针对受这些稀有分子影响的通路的小分子的先导 变体和miRNAs(项目3)。这一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)和一个基因工程小鼠和 老年病理学核心(核心B)。利用我们丰富的遗传资源，包括一些来自我们制药的资源 合作伙伴，Regeneron，我们还将进一步确认和验证一些遗传变异并发现 另外，新的基因变异和相关的途径对人类的长寿非常重要。建议数 该项目将大大提高我们对保护长寿路径的重要性的理解， 到目前为止，主要是在人类衰老的模式生物中进行识别和研究。重要的是，这种基因与药物有关 合作项目将是第一个使用健康老龄化罕见个体的遗传学作为指南的项目 针对衰老本身而不是其复合性疾病的治疗方法的发展 预防、延缓发病和进展，甚至可能逆转许多与年龄有关的多种疾病。