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

GH/IGF1信号通路对长寿miRNA的作用

• 批准号: 9581485
• 负责人: MICHAL Mateusz MASTERNAK
• 金额: $ 14.9万
• 依托单位: UNIVERSITY OF CENTRAL FLORIDA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-30 至 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9581485
• 关键词: Adipocytes; Adipose tissue; Adolescent; Adult; Age; Aging; Animals; Atherosclerosis; Blood Circulation; Caloric Restriction; Cell Nucleus; Cells; Development; Diabetes Mellitus; Diet; Disease; Dwarfism; Elderly; Fatty acid glycerol esters; Follow-Up Studies; Gene Expression; Genes; Genetic; Genetic Transcription; Genotype; Glucose Intolerance; Goals; Growth and Development function; Hormone replacement therapy; Human; IGF1 gene; In Vitro; Incidence; Inflammatory; Insulin; Insulin Resistance; Insulin-Like Growth Factor I; Life; Life Style; Link; Longevity; Mediating; Mesenchymal Stem Cells; Metabolic; Metabolic syndrome; MicroRNAs; Mus; Obesity; Organ; Pathway interactions; Phenotype; Phosphorylation; Play; Population; Predisposition; Process; Production; Publishing; Race; Rattus; Regulation; Research; Role; Serum; Signal Pathway; Signal Transduction; Somatotropin; Source; Testing; Time; Transcription Process; Transcriptional Activation; Transplantation; Untranslated RNA; adipokines; adiponectin; age related; base; cytokine; deep sequencing; exosome; growth hormone deficiency; healthspan; healthy aging; hormonal signals; improved; insulin sensitivity; insulin signaling; postnatal; protective factors; receptor; regenerative; resilience; response

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.

该提案的长期目标是鉴定循环微小 RNA (miRNA) 作为潜在的幼体 介导出生后发育过程中生长激素信号对健康影响的保护因素 老化。随着老年人口的不断增加，与年龄相关的疾病发病率不断上升 包括代谢综合征、动脉粥样硬化疾病、胰岛素抵抗和糖尿病。多项研究 对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 限制可以减少脂肪体积，提高胰岛素敏感性并延长寿命。然而，我们的 对长寿艾姆斯侏儒 (df/df) 小鼠的研究表明，这些生长激素缺乏的动物 无论肥胖倾向如何，脂肪组织功能的改变都会促进健康表型 老化。我们提出一般假设假设循环 miRNA 种类的水平发生变化 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传导与衰老控制联系起来。在 在拟议的研究中，我们将研究生长激素（GH）和脂联素对 循环系统和胰岛素靶器官中推定的长寿 miRNA。 为了检验我们的假设，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表达的机制 艾姆斯侏儒小鼠和正常小鼠中推定的长寿 miRNA。 2. 确定 MSC 在多大程度上有助于循环推定的长寿 miRNA 的释放 对 GH/IGF-1 或脂联素的反应。调查df/df血清中外泌体的含量有多少 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。