GENERATION OF TISSUE-SPECIFIC KNOCKOUT MICE

组织特异性基因敲除小鼠的产生

• 批准号: 8049159
• 负责人: John Joseph Kopchick
• 金额: $ 33.27万
• 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/8049159
• 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; 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) 是一种致糖尿病分子，即它抑制胰岛素作用，导致胰岛素抵抗 和糖尿病。 GH 的致糖尿病作用可以在 GH 表达相对较高的转基因小鼠中观察到。 GH 水平。这些动物还拥有高水平的胰岛素，如生长因子一 (IGF-1) 和胰岛素， 存在胰岛素抵抗且寿命短。在人类中，肢端肥大症患者的 GH 和 IGF-1 水平升高，通常是胰岛素抵抗，许多人会患上糖尿病。因此，升高 小鼠和人类的 GH 水平都会导致胰岛素抵抗。相反，小鼠是在我们的 实验室缺乏 GH 受体（GHR/BP-/- 小鼠），因此缺乏 GH 作用。这些老鼠是侏儒， IGF-1 和胰岛素水平较低，对胰岛素极其敏感，并且寿命较长。 此外，胰岛素或 IGF-1 信号系统的破坏也会导致线虫的寿命延长， 酵母、果蝇和其他 GH/IGF-1 信号减弱的小鼠品系。因此，人们会预测 通过抑制 GH/IGF-1 信号传导来增加胰岛素敏感性将导致动物的胰岛素敏感性增加 寿命。三种胰岛素和 GH 敏感组织是肝脏、白色脂肪组织 (WAT) 和肌肉。经过 提高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 GHR/BP-/- 小鼠的寿命延长是由于 GHaction 减少和 随后胰岛素反应组织中的胰岛素敏感性增加。为了检验这个假设，我们将 选择性破坏肝脏、WAT 和肌肉中的 GHR 基因，以确定它们各自对 总体胰岛素敏感性和寿命。我们期望在三个组织中发现胰岛素敏感性的改善- 特定基因破坏了小鼠品系，这反过来又会延长寿命。一旦三个鼠标线 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个体组织对整体胰岛素敏感性的重要性。 延长寿命的因素。此外，这些数据将有助于增进对分子的理解 以及衰老过程中的细胞变化。最后，结果可能会导致干预措施的延长 生命或延缓与年龄相关的疾病和/或残疾的发生。 相关性（参见说明）： 缺乏 GH 作用已被证明可以提高胰岛素敏感性并延长寿命。去除 正如本提案中概述的那样，GH 在肝脏、脂肪和肌肉中的作用将有助于识别对生命至关重要的器官。 改善胰岛素敏感性并延长寿命。