Determination of the mechanistic targets of metformin

项目总结 糖尿病影响了3000多万美国人，占总人口的9.4%，令人震惊。 糖尿病会导致血糖水平升高。随着时间的推移，体内高血糖的存在 会对各种组织造成损害。二甲双胍是美国食品和药物管理局的一种药物，通常用作fi的第一线治疗 2型糖尿病的治疗。它的主要作用是使组织对胰岛素更敏感，从而 增强由胰腺产生的胰岛素的作用，以平衡降低血糖水平。 然而，重要的是，二甲双胍也可以延长寿命，延缓酵母衰老的开始 哺乳动物。在高等生物体中，它还可以降低心血管疾病的风险，并抑制 肿瘤生长。令人惊讶的是，考虑到自1958年以来它在人类身上的临床应用，确切的分子机制 其广泛的健康益处的潜在原因尚不清楚。此催化剂项目旨在 首次阐明了二甲双胍的直接细胞蛋白靶点。我们令人鼓舞的初步结果 数据显示，我们可以将尖端的蛋白质组学方法应用于这种结合事件， 道路。在这个项目中，我们希望将这种非常有希望的方法扩展到不同的生物体。 通过在多种系统发育不同的模式生物中识别二甲双胍的分子靶点 (酵母、蠕虫、苍蝇、老鼠和人类)，我们将能够集中研究至关重要的蛋白质， 同时筛选出非特异性粘结剂。我们将对已发现的目标进行机械测试 通过使用各种分析方法进行的功能损失和功能增益实验，这些实验将作为项目进行调整 预付款。在验证了少数强大的候选二甲双胍结合蛋白后，我们将测试 这些在哺乳动物中很有希望的候选基因通过使转基因小鼠在相关的 编码这些蛋白质的基因。我们预计特定的机械性亚甲基化的鉴定 目标将促进治疗糖尿病和促进健康老龄化的新疗法的开发。 这两个目标都与NIDDK和更广泛的NIH的核心任务密切相关。

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.