GENERATION OF TISSUE-SPECIFIC KNOCKOUT MICE

组织特异性基因敲除小鼠的产生

• 批准号: 7651569
• 负责人: John Joseph Kopchick
• 金额: $ 31.91万
• 依托单位: SOUTHERN ILLINOIS UNIVERSITY SCH OF MED
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7651569
• 关键词: Ablation; Acromegaly; Adipose tissue; Aging; Aging-Related Process; Animals; Body Composition; Body Weight; Characteristics; DNA; Data; Diabetes Mellitus; Disease; ES Cell Line; Elements; Endocrine; Excision; Fatty acid glycerol esters; Fibrinogen; GHR gene; Gene Expression; Generations; Genes; Glucose; Growth; Growth Hormone Receptor; Health; Hormone Responsive; Hormones; Human; Individual; Infiltration; Instruction; Insulin; Insulin Resistance; Insulin-Like Growth Factor I; Intervention; Knockout Mice; Laboratories; LacZ Genes; Lead; Leptin; Life; Life Extension; Liver; Longevity; Measures; Metabolic; Michigan; Molecular; Mus; Muscle; Nonesterified Fatty Acids; Obesity; Organ; Patients; Performance; Physiological; Pituitary Gland; Play; Production; Prolactin; Reporter; Reporting; Repression; Role; Signal Transduction; Somatomedins; Somatotropin; Specificity; Study Section; System; Testing; Time; Tissues; Transgenic Mice; Triglycerides; Universities; Yeasts; adiponectin; age related; disability; fly; homologous recombination; improved; insulin sensitivity; insulin signaling; insulin tolerance; macrophage; mouse model; reproductive; somatotropin-binding protein

Growth Hormone (GH) is a diabetogenic molecule, i.e., it inhibits insulin action resulting in insulin resistance and diabetes. The diabetogenic effect of GH can be seen in GH transgenic mice that express relatively high levels of GH. These animals also possess high levels of insulin like growth factor one (IGF-1) and insulin, are insulin resistant and have short life spans. In humans, patients with acromegaly possess elevated levels of GH and IGF-1, are typically insulin resistance and many will develop diabetes. Thus, elevated levels of GH in both mice and humans results in insulin resistance. Conversely, mice were developed in our laboratory that lack the GH receptor (GHR/BP-/- mice) and therefore GH action. These mice are dwarf, possess low levels of IGF-1 and insulin, are extremely insulin sensitive and have an extended life span. Furthermore, disruption of the insulin or IGF-1 signaling system also leads to extended life spans in worms, yeast, flies, and other mouse lines with reduced GH/IGF-1 signaling. Thus, one would predict that increasing insulin sensitivity through repression of GH/IGF-1 signaling will result in animals with increased life span. Three insulin and GH sensitive .tissues are the liver, white adipose tissue (WAT) and muscle. By increasing insulin sensitivity in these tissues, one may increase the animal's life span. We hypothesize that the life span extension seen in the GHR/BP-/- mouse is due to decreased GHaction and consequent increased insulin sensitivity in insulin responsive tissues. To test this hypothesis, we will selectively disrupt the GHR gene in liver, WAT, and muscle to determine their individual contributions to overall insulin sensitivity and longevity. We expect to find improved insulin sensitivity in the three tissue- specific gene disrupted mouse lines, which, in turn, will increase longevity. Once the three mouse lines are generated, we will also assess a variety of growth, endocrine, physiological and metabolic parameters. Collectively, this data will help establish the importance of individual tissues on overall insulin sensitivity as a contributing factor to increased life span. Also, the data will help advance the understanding of molecular and cellular changes that underlie the aging process. Finally, the results may lead to interventions to extend life or delay the onset of age-related diseases and/or disabilities. RELEVANCE (See instructions): The absence of GH action has been shown to improve insulin sensitivity and increase life span. Removal of GH action in liver, fat, and muscle, as outlined in this proposal will help identify organs that are important for improved insulin sensitivity and life extension.

生长激素(GH)是一种致糖尿病的分子，即它抑制导致胰岛素抵抗的胰岛素作用。 还有糖尿病。在表达相对较高的生长激素转基因小鼠中可以看到生长激素的促糖尿病作用。 生长激素水平。这些动物还拥有高水平的胰岛素样生长因子1(IGF-1)和胰岛素， 对胰岛素有抵抗力，寿命短。在人类中，肢端肥大症患者的 生长激素和胰岛素样生长因子-1的水平通常是胰岛素抵抗，许多人会患上糖尿病。因此，提升了 小鼠和人类体内的生长激素水平都会导致胰岛素抵抗。相反，小鼠是在我们的 缺乏生长激素受体的实验室(GHR/BP-/-小鼠)，因此GH作用。这些老鼠是矮小的， 胰岛素样生长因子-1和胰岛素水平低，对胰岛素高度敏感，寿命延长。 此外，胰岛素或IGF-1信号系统的破坏也会延长蠕虫的寿命， 酵母、苍蝇和其他生长激素/胰岛素样生长因子-1信号降低的小鼠品系。因此，人们可以预测到 通过抑制GH/IGF-1信号增加胰岛素敏感性将导致动物体内 寿命。对胰岛素和生长激素敏感的三种组织是肝脏、白色脂肪组织(WAT)和肌肉。通过 增加这些组织中的胰岛素敏感性，可能会延长动物的寿命。我们假设 在GHR/BP-/-小鼠中看到的寿命延长是由于温室气体活动减少和 随之而来的是胰岛素反应组织中胰岛素敏感性的增加。为了检验这一假设，我们将 选择性干扰肝脏、Wat和肌肉中的GHR基因，以确定它们对 总体而言，胰岛素敏感性和寿命。我们希望在这三个组织中发现胰岛素敏感性的改善- 特定的基因扰乱了小鼠的品系，这反过来又会延长寿命。一旦三条鼠标线被 生成后，我们还将评估各种生长、内分泌、生理和代谢参数。 总的来说，这些数据将有助于确定单个组织对整体胰岛素敏感性的重要性 有助于延长寿命的因素。此外，这些数据将有助于促进对分子的理解 以及作为衰老过程基础的细胞变化。最后，结果可能会导致干预延长 或延缓与年龄有关的疾病和/或残疾的发生。 相关性(请参阅说明)： 没有生长激素的作用已被证明可以改善胰岛素敏感性和延长寿命。删除 GH在肝脏、脂肪和肌肉中的作用，如本提案中所概述的，将有助于确定哪些器官对 改善胰岛素敏感性，延长寿命。