GENERATION OF TISSUE-SPECIFIC KNOCKOUT MICE

组织特异性基因敲除小鼠的产生

基本信息

项目摘要

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,也就是说,它抑制胰岛素的作用,导致胰岛素抵抗

项目成果

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John Joseph Kopchick其他文献

John Joseph Kopchick的其他文献

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{{ truncateString('John Joseph Kopchick', 18)}}的其他基金

Diabetes Institute Summer Interprofessional Research Experience (DISIRE) for Undergraduates
糖尿病研究所本科生暑期跨专业研究体验 (DISIRE)
  • 批准号:
    10331413
  • 财政年份:
    2022
  • 资助金额:
    $ 31.91万
  • 项目类别:
Combining GHR antagonism with life extending compounds: a search for synergies
将 GHR 拮抗作用与延长生命的化合物相结合:寻求协同作用
  • 批准号:
    10738834
  • 财政年份:
    2018
  • 资助金额:
    $ 31.91万
  • 项目类别:
Modulating Growth Hormone Action as a Target for Improved Health and Longevity
调节生长激素作用作为改善健康和长寿的目标
  • 批准号:
    9770741
  • 财政年份:
    2018
  • 资助金额:
    $ 31.91万
  • 项目类别:
Modulating Growth Hormone Action as a Target for Improved Health and Longevity
调节生长激素作用作为改善健康和长寿的目标
  • 批准号:
    10442723
  • 财政年份:
    2018
  • 资助金额:
    $ 31.91万
  • 项目类别:
Creation and characterization of GH binding protein gene disrupted mice
GH 结合蛋白基因破坏小鼠的创建和表征
  • 批准号:
    7303768
  • 财政年份:
    2007
  • 资助金额:
    $ 31.91万
  • 项目类别:
GENERATION OF TISSUE-SPECIFIC KNOCKOUT MICE
组织特异性基因敲除小鼠的产生
  • 批准号:
    8377761
  • 财政年份:
  • 资助金额:
    $ 31.91万
  • 项目类别:
GENERATION OF TISSUE-SPECIFIC KNOCKOUT MICE
组织特异性基因敲除小鼠的产生
  • 批准号:
    8248259
  • 财政年份:
  • 资助金额:
    $ 31.91万
  • 项目类别:
GENERATION OF TISSUE-SPECIFIC KNOCKOUT MICE
组织特异性基因敲除小鼠的产生
  • 批准号:
    8049159
  • 财政年份:
  • 资助金额:
    $ 31.91万
  • 项目类别:
GENERATION OF TISSUE-SPECIFIC KNOCKOUT MICE
组织特异性基因敲除小鼠的产生
  • 批准号:
    8448204
  • 财政年份:
  • 资助金额:
    $ 31.91万
  • 项目类别:

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肢端肥大症患者姿势和静态平衡的生物力学分析
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用于治疗肢端肥大症的一流抗体疗法
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    10082375
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    2020
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Personalized Lanreotide Treatment for Acromegaly
肢端肥大症的个性化兰瑞肽治疗
  • 批准号:
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New Approaches to the Evaluation and Treatment of Acromegaly
肢端肥大症评估和治疗的新方法
  • 批准号:
    9924534
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New Approaches to the Evaluation and Treatment of Acromegaly
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    9750716
  • 财政年份:
    2017
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    $ 31.91万
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Development of a long-acting growth hormone antagonist to address the unmet need for treatment in acromegaly
开发长效生长激素拮抗剂,以满足肢端肥大症治疗未满足的需求
  • 批准号:
    MR/M015491/1
  • 财政年份:
    2015
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    $ 31.91万
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CLINICAL TRIAL: GROWTH HORMONE FEEDBACK IN PATIENTS WITH ACROMEGALY, TYPE 2 DIAB
临床试验:2 型 DIAB 肢端肥大症患者的生长激素反馈
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    8174443
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    $ 31.91万
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New Approaches to the Evaluation and Treatment of Acromegaly
肢端肥大症评估和治疗的新方法
  • 批准号:
    7990198
  • 财政年份:
    2009
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    $ 31.91万
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Elucidation of the role of the molecular chaperone AIP in familial acromegaly
阐明分子伴侣 AIP 在家族性肢端肥大症中的作用
  • 批准号:
    G0701307/1
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    2008
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    $ 31.91万
  • 项目类别:
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