Role of GH/IGF1 signaling pathway on pro-longevity miRNAs

这项提议的长期目标是确定循环中的微小RNA(MiRNAs)是潜在的幼体 促生长激素信号在出生后发育过程中对健康人群影响的保护因素 衰老。随着老年人口的增长，与年龄有关的疾病的发病率也在增加 包括代谢综合征、动脉粥样硬化性疾病、胰岛素抵抗和糖尿病。几项研究 与小鼠和大鼠的研究表明，肥胖会导致胰岛素抵抗，并对寿命产生负面影响。卡路里 节食可以减少脂肪的体积，改善胰岛素敏感性，延长寿命。然而，我们的 对长寿的Ames侏儒(DF/DF)小鼠的研究表明，这些生长激素缺乏的动物有 脂肪组织促进健康表型的功能改变与肥胖易感性无关 衰老。我们提出了一个普遍的假设，即循环中miRNA物种水平的变化 由脂肪组织来源的间充质干细胞分泌，将发育过程中的激素信号与衰老的控制联系起来。在……里面 在拟议的研究中，我们将研究生长激素(GH)和脂联素对 循环和胰岛素靶器官中推定的有利于长寿的miRNA。 为了验证我们的假设，我们提出了四个具体目标： 1.确定GH/IGF-1和脂联素信号通路调节血管内皮生长因子表达的机制 Ames矮小和正常小鼠中推测的有利于长寿的miRNAs。 2.确定MSCs在多大程度上促进了循环中可能的长寿miRNAs的释放 对GH/IGF-1或脂联素的反应。研究DF/DF血清中含有外切体的程度 小鼠可以在体外渗透靶细胞，以减少促炎细胞因子和脂肪因子的产生。

The long-goal of this proposal is to identify circulating micro RNA (miRNAs) as potential juvenile protective factors that mediate the effects of somatotropic signaling during postnatal development on healthy aging. With the growing population of elderly people, there is growing incidence of age-related diseases including metabolic syndrome, atherosclerotic disease, insulin resistance and diabetes mellitus. Several studies with mice and rats indicated that obesity causes insulin resistance and has negative effects on longevity. Calorie restriction decreases the volume of fat, improves insulin sensitivity and extends longevity. However, our studies with long-living Ames dwarf (df/df) mice indicated that these growth hormone deficient animals have altered function of adipose tissue promoting healthy phenotype regardless of predisposition to obesity during aging. We propose the general hypothesis hypothesis that alterations in the levels of circulating miRNA species secreted by adipose tissue-derived MSCs link hormonal signaling during development with control of aging. In the proposed studies, we will investigate the effects of growth hormone (GH) and adiponectin on the levels of putative pro-longevity miRNA in circulation and insulin target organs. To test our hypothesis we propose four specific aims: 1. Determine the mechanism by which GH/IGF-1 and adiponectin signaling pathways regulate expression of putative pro-longevity miRNAs in Ames dwarf and normal mice. 2. Determine to what extent MSCs contribute to the release of circulating putative pro-longevity miRNAs in response to GH/IGF-1 or adiponectin. Investigate to what extent exosomes contained in the serum of df/df mice can infiltrate target cells in vitro to reduce production of pro-inflammatory cytokines and adipokines.