Leveraging snakes' extreme physiology to modulate human beta-cell function

项目总结 糖尿病困扰着全球3.66亿人，每7秒就有一人死亡，占死亡人数的80% 发生在低收入和中等收入国家。此外，糖尿病还造成4650亿美元的医疗成本 每年都有。1型和2型糖尿病的主要病理机制是胰岛素分泌功能障碍和死亡。 β细胞。我们寻找预防β细胞功能障碍和死亡的机制，并使失去的人再生 β细胞团，引导我们找到了具有极端新陈代谢生理的生物。在几百万年的时间里 进化，极端的生物已经出现，它们在对人类有害的条件下茁壮成长。一 这样的有机体是狂食的蛇，它们的β细胞在 对人类β细胞来说是病态的。我们已经确定了一组这样的蛇，它们的β细胞可以承受 低氧，高氧，脂毒应激，并经历非病理性肥大时，这些蛇吃他们的 丰盛的一餐。此外，我们的数据表明，这些蛇拥有能够诱导合意的分子 哺乳动物β细胞的表型。这项提议的目标是确定能够增强 人类β细胞的质量和功能。我们还建议描绘出构成 这些蛇的β细胞表现出的其他极端表型，最终目的是操纵 这些途径在人类β细胞中使用小分子。

PROJECT SUMMARY Diabetes afflicts 366 million worldwide and results in one death every 7 seconds, with 80% of deaths occurring in low- and middle-income countries. Additionally, diabetes creates $465 billion in healthcare costs every year. Central to the pathology of type 1 and 2 diabetes is dysfunction and death of insulin-producing beta cells. Our search for mechanisms to prevent beta-cell dysfunction and death, and to regenerate the lost beta-cell mass, led us to organisms with extreme metabolic physiology. Through millions of years of evolution, extreme organisms have arisen that thrive under conditions otherwise pathological to humans. One such group of organisms are binge-eating snakes, whose beta cells survive under conditions that are pathological to human beta cells. We have identified a group of such snakes whose beta cells can withstand hypoxia, hyperoxia, lipotoxic stress, and undergo non-pathologic hypertrophy when these snakes eat their large meals. Further, our data suggests that these snakes possess molecules that can induce desirable phenotypes in mammalian beta cells. The goal of this proposal is to identify the molecules that enhance human beta-cell mass and function. We also propose to delineate the signaling pathways that underlie the other extreme phenotypes exhibited by the beta cells of these snakes, with the ultimate aim of manipulate these pathways in human beta cells using small molecules.