Determination of the mechanistic targets of metformin

二甲双胍作用机制目标的确定

• 批准号: 10226321
• 负责人: Akhilesh Basi Reddy
• 金额: $ 79.88万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-30 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10226321
• 关键词: Affect; Aging; American; Animal Model; Binding; Binding Proteins; Biological Assay; Blood Glucose; Clinical; Code; Data; Development; Diabetes Mellitus; Disease; Event; Genes; Glucose; Goals; Health Benefit; Home; Human; Insulin; Longevity; Mammals; Metformin; Mission; Molecular; Molecular Target; Mus; National Institute of Diabetes and Digestive and Kidney Diseases; Non-Insulin-Dependent Diabetes Mellitus; Organism; Pancreas; Pharmaceutical Preparations; Phylogenetic Analysis; Population; Proteins; Proteomics; Testing; Time; Tissues; Transgenic Mice; United States National Institutes of Health; Validation; Yeasts; cardiovascular disorder risk; catalyst; experimental study; fly; gain of function; healthy aging; novel therapeutics; screening; tumor growth

PROJECT SUMMARY Diabetes affects over 30 million Americans, which represents a staggering 9.4% of the population. Diabetes causes an elevated blood glucose level. Over time, the presence of high glucose in the body results in damage to various tissues. Metformin is an FDA drug commonly used as a first line therapy for the treatment of Type 2 Diabetes. It mainly acts to make tissues more sensitive to insulin, thereby enhancing the effects of insulin produced by the pancreas to homeostatically lower blood glucose levels. Importantly, however, Metformin also prolongs lifespan and delays the onset of aging from yeast to mammals. In higher organisms, it additionally reduces the risk of cardiovascular disease and inhibits tumor growth. Astoundingly, given its clinical use in humans since 1958, the exact molecular mechanisms underlying its wide-ranging health benefits are unknown. This Catalyst project is directed towards elucidating the direct cellular protein targets of Metformin for the first time. Our encouraging preliminary data shows that we can apply cutting-edge proteomics approaches to such binding events in an unbiased way. In this project, we wish to extend this extremely promising approach to a diverse range of organisms. By identifying molecular targets of Metformin in a variety of phylogenetically different model organisms (yeast, worms, flies, mouse, and humans), we will be able to home in on proteins of crucial importance, while simultaneously screening out non-specific binders. We will mechanistically test discovered targets by loss- and gain-of-function experiments using various assays, which will be adapted as the project advances. After validation of a small number of strong candidate Metformin binding proteins, we will test these promising candidates in mammals by making transgenic mice harboring deletions in the relevant genes coding for these proteins. We anticipate that the identification of specific mechanistic Metformin targets will facilitate the development of novel therapeutics to treat diabetes and promote healthy aging. Both of these goals are closely aligned with the core missions of NIDDK, and the wider NIH.

项目摘要 糖尿病会影响超过3000万美国人，这占人口的惊人。 糖尿病会导致血糖水平升高。随着时间的流逝，体内高葡萄糖的存在 导致对各种组织的损害。二甲双胍是一种FDA药物，通常用作第一线治疗 2型糖尿病的治疗。它主要使组织对胰岛素更敏感，从而 增强胰腺产生的胰岛素对稳态降低血糖水平的作用。 然而，重要的是，二甲双胍也延长了寿命，并延迟了从酵母到 哺乳动物。在较高的生物体中，它还降低了心血管疾病的风险并抑制 肿瘤生长。惊人的是，鉴于自1958年以来其在人类中的临床用途，确切的分子机制 其广泛的健康益处的基础尚不清楚。这个催化剂项目针对 首次阐明二甲双胍的直接细胞蛋白靶标。我们令人鼓舞的初步 数据表明，我们可以在公正的情况下应用尖端的蛋白质组学方法对此类结合事件 方式。在这个项目中，我们希望将这种极其有望的方法扩展到潜水员的各种生物。 通过识别多种系统发育不同模型生物中二甲双胍的分子靶标 （酵母，蠕虫，苍蝇，老鼠和人类），我们将能够融入至关重要的蛋白质中， 同时筛选出非特异性粘合剂。我们将机械测试发现的目标 通过使用各种测定的功能和功能损益实验，该实验将被改编为项目 进步。验证了少量强候选二甲双胍结合蛋白后，我们将测试 这些有希望的哺乳动物候选人通过使相关删除的转基因小鼠在 编码这些蛋白质的基因。我们预计特定机械二甲双胍的鉴定 靶标将促进新型疗法的发展，以治疗糖尿病并促进健康的衰老。 这两个目标都与NIDDK和更广泛的NIH的核心任务紧密相符。