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的致糖尿病效应可以在表达相对高的GH转基因小鼠中观察到。 GH水平。这些动物还具有高水平的胰岛素样生长因子1（IGF-1）和胰岛素， 具有胰岛素抗性，寿命短。在人类中，肢端肥大症患者具有升高的 生长激素和IGF-1水平，通常是胰岛素抵抗，许多人会发展成糖尿病。因此， 小鼠和人的GH水平导致胰岛素抵抗。相反，小鼠在我们的研究中被开发出来， 实验室缺乏GH受体（GHR/BP-/-小鼠），因此GH的作用。这些老鼠是侏儒， 具有低水平的IGF-1和胰岛素，对胰岛素非常敏感，寿命延长。 此外，胰岛素或IGF-1信号系统的破坏也导致蠕虫寿命延长， 酵母、果蝇和其他GH/IGF-1信号转导减少的小鼠品系。因此，人们可以预测， 通过抑制GH/IGF-1信号传导而增加胰岛素敏感性将导致动物具有增加的 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。通过 增加这些组织中的胰岛素敏感性，可以增加动物的寿命。我们假设 在GHR/BP-/-小鼠中观察到的寿命延长是由于GH作用降低， 从而增加胰岛素应答组织中的胰岛素敏感性。为了验证这个假设，我们将 选择性地破坏肝脏、WAT和肌肉中的GHR基因，以确定它们对 整体胰岛素敏感性和寿命。我们希望在这三种组织中发现改善的胰岛素敏感性- 特定基因破坏小鼠品系，这反过来又会增加寿命。一旦三条鼠标线 我们还将评估各种生长、内分泌、生理和代谢参数。 总的来说，这些数据将有助于建立个体组织对整体胰岛素敏感性的重要性， 增加寿命的因素。此外，这些数据将有助于促进对分子生物学的理解。 以及衰老过程中的细胞变化最后，研究结果可能会导致干预措施的扩大， 这些措施可延长老年人的生命或延迟与年龄有关的疾病和/或残疾的发作。 相关性（参见说明）： 缺乏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。去除 生长激素在肝脏，脂肪和肌肉中的作用，如本提案所述，将有助于确定重要的器官， 改善胰岛素敏感性和延长寿命。