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。在表达相对较高的GH转基因小鼠中，GH的糖尿病生成作用可见 GH的水平。这些动物还具有高水平的胰岛素，例如生长因子一（IGF-1）和胰岛素， 具有胰岛素耐药性，寿命短。在人类中，肢端肥大的患者具有升高 GH和IGF-1的水平通常是胰岛素抵抗，许多会产生糖尿病。因此，提高了 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 缺乏GH受体（GHR/BP - / - 小鼠）的实验室，因此是GH作用。这些老鼠是矮人， 具有低水平的IGF-1和胰岛素，对胰岛素非常敏感，其寿命延长。 此外，胰岛素或IGF-1信号系统的破坏也导致蠕虫的寿命延长， 酵母，苍蝇和其他小鼠线，具有降低的GH/IGF-1信号传导。因此，人们会预测 通过抑制GH/IGF-1信号来提高胰岛素敏感性将导致动物增加 寿命。三种胰岛素和GH敏感的。感染者是肝脏，白色脂肪组织（WAT）和肌肉。经过 这些组织中胰岛素敏感性提高，可能会增加动物的寿命。我们假设 在GHR/BP - / - 小鼠中看到的寿命延长是由于ghaction降低和 因此，胰岛素反应性组织中胰岛素敏感性提高。为了检验这一假设，我们将 有选择地破坏肝脏，WAT和肌肉中的GHR基因，以确定其个人对 总体胰岛素敏感性和寿命。我们期望在三个组织中发现提高胰岛素敏感性 特定的基因破坏了小鼠系，这又会增加寿命。一旦三个鼠标线 生成的，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总体胰岛素敏感性的重要性 促成增加寿命的因素。此外，数据将有助于提高对分子的理解 和衰老过程的基础的细胞变化。最后，结果可能导致干预措施扩展 生命或延迟与年龄有关的疾病和/或残疾的发作。 相关性（请参阅说明）： 已经证明缺乏GH作用可以提高胰岛素敏感性并增加寿命。去除 如本提案中概述的那样 改善胰岛素的敏感性和寿命延长。