Regulation of Akt and glucose transport by prolactin

催乳素对 Akt 和葡萄糖转运的调节

基本信息

  • 批准号:
    6874981
  • 负责人:
  • 金额:
    $ 24.7万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2003
  • 资助国家:
    美国
  • 起止时间:
    2003-07-01 至 2007-04-30
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Lactation is of great importance to survival of newborn animals. Prolactin plays a critical role in this process by regulating the differentiation of mammary epithelial cells into secretory epithelial cells. Much of the research on prolactin signal transduction has focused upon its role in regulating the transcription of milk protein genes. However, since milk is 25 - 30% fat and about 3% lactose, pathways that control glucose availability and lipid biosynthesis are likely to be critical for optimal milk production. Our previous studies indicate that the serine/threonine protein kinase Akt, plays a critical role in suppressing apoptosis in the involuting mammary gland. We hypothesize that prolactin regulates glucose transport and lipid biosynthesis and the Akt protein kinase is required for prolactin-mediated activation of glucose transport. In this grant we propose to map the region(s) of the prolactin receptor that are required for activation of Akt and glucose transport. We will focus on phosphorylated tyrosine residues because the binding of signaling molecules to these sites often regulates their activation, particularly SH2 domain containing molecules. We will use a chimeric prolactin receptor whose activation can be controlled by a chemical dimerizer. This chimeric receptor will be expressed in mammary epithelial cells to map the regions that regulate glucose transport and Akt activation. Transgenic mice will be generated that express the chimeric prolactin receptor in the mammary gland to test the function of specific receptor mutants. These studies will be done under conditions where the production of prolactin by the pituitary is blocked thereby preventing activation of the endogenous prolactin receptor. Mammary gland development is altered in Src-/- mice but not in Fyn-/- mice. Primary mammary epithelial cells derived from Src-/- and Fyn-/- mice will be used to determine the role of these kinases in regulating Akt activation, and glucose transport. We will also test the role of specific signaling molecules (c-Cbl, Cbl-B, IRS-1, Gab2, Gab3, SHP 1, and SHP2) in regulating the PI3-kinase/Akt pathway and glucose transport. Finally, we will determine the mechanisms by which prolactin increases glucose transport in mammary epithelial cells. Until now, the mechanisms by which glucose transport in mammary epithelial cells is regulated have remained a mystery. These studies should provide important information about other roles for prolactin in the mammary gland and identify the mechanisms by which prolactin regulates these diverse processes.
描述(由申请人提供): 哺乳期对于新生动物的生存非常重要。催乳素通过调节乳腺上皮细胞向分泌性上皮细胞的分化,在此过程中发挥关键作用。关于催乳素信号转导的许多研究都集中在其在调节乳蛋白基因转录中的作用。然而,由于牛奶含有 25 - 30% 的脂肪和约 3% 的乳糖,因此控制葡萄糖利用率和脂质生物合成的途径可能对于最佳牛奶生产至关重要。我们之前的研究表明,丝氨酸/苏氨酸蛋白激酶 Akt 在抑制消退乳腺细胞凋亡中发挥着关键作用。我们假设催乳素调节葡萄糖转运和脂质生物合成,并且催乳素介导的葡萄糖转运激活需要 Akt 蛋白激酶。在这项资助中,我们建议绘制激活 Akt 和葡萄糖转运所需的催乳素受体区域。我们将重点关注磷酸化酪氨酸残基,因为信号分子与这些位点的结合通常会调节它们的激活,特别是含有 SH2 结构域的分子。我们将使用嵌合催乳素受体,其激活可以通过化学二聚剂控制。这种嵌合受体将在乳腺上皮细胞中表达,以绘制调节葡萄糖转运和 Akt 激活的区域。将产生在乳腺中表达嵌合催乳素受体的转基因小鼠,以测试特定受体突变体的功能。这些研究将在垂体产生催乳素被阻断的条件下进行,从而防止内源性催乳素受体的激活。 Src-/- 小鼠的乳腺发育发生改变,但 Fyn-/- 小鼠的乳腺发育没有改变。来自 Src-/- 和 Fyn-/- 小鼠的原代乳腺上皮细胞将用于确定这些激酶在调节 Akt 激活和葡萄糖转运中的作用。我们还将测试特定信号分子(c-Cbl、Cbl-B、IRS-1、Gab2、Gab3、SHP 1 和 SHP2)在调节 PI3 激酶/Akt 通路和葡萄糖转运中的作用。最后,我们将确定催乳素增加乳腺上皮细胞中葡萄糖转运的机制。到目前为止,乳腺上皮细胞中葡萄糖转运的调节机制仍然是个谜。这些研究应该提供有关催乳素在乳腺中其他作用的重要信息,并确定催乳素调节这些不同过程的机制。

项目成果

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STEVEN M ANDERSON其他文献

STEVEN M ANDERSON的其他文献

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{{ truncateString('STEVEN M ANDERSON', 18)}}的其他基金

Lifestyle associated reactive metabolites and their negative impact on breast cancer risk
生活方式相关的反应性代谢物及其对乳腺癌风险的负面影响
  • 批准号:
    10206074
  • 财政年份:
    2020
  • 资助金额:
    $ 24.7万
  • 项目类别:
TISSUE CULTURE/ MAb CORE
组织培养/单克隆抗体核心
  • 批准号:
    8616657
  • 财政年份:
    2014
  • 资助金额:
    $ 24.7万
  • 项目类别:
Is GLUT1 required for tumor growth and the Warburg Effect?
肿瘤生长和瓦尔堡效应需要 GLUT1 吗?
  • 批准号:
    8505396
  • 财政年份:
    2011
  • 资助金额:
    $ 24.7万
  • 项目类别:
Endocrine Network for Undergraduate Research and Carrier Development Opportunitie
本科生研究和载体发展机会内分泌网络
  • 批准号:
    8626413
  • 财政年份:
    2011
  • 资助金额:
    $ 24.7万
  • 项目类别:
Is GLUT1 required for tumor growth and the Warburg Effect?
肿瘤生长和瓦尔堡效应需要 GLUT1 吗?
  • 批准号:
    8188853
  • 财政年份:
    2011
  • 资助金额:
    $ 24.7万
  • 项目类别:
Endocrine Network for Undergraduate Research and Carrier Development Opportunitie
本科生研究和载体发展机会内分泌网络
  • 批准号:
    8821630
  • 财政年份:
    2011
  • 资助金额:
    $ 24.7万
  • 项目类别:
Endocrine Network for Undergraduate Research and Carrier Development Opportunitie
本科生研究和载体发展机会内分泌网络
  • 批准号:
    8233329
  • 财政年份:
    2011
  • 资助金额:
    $ 24.7万
  • 项目类别:
Endocrine Network for Undergraduate Research and Carrier Development Opportunitie
本科生研究和载体发展机会内分泌网络
  • 批准号:
    8460849
  • 财政年份:
    2011
  • 资助金额:
    $ 24.7万
  • 项目类别:
Is GLUT1 required for tumor growth and the Warburg Effect?
肿瘤生长和瓦尔堡效应需要 GLUT1 吗?
  • 批准号:
    8333385
  • 财政年份:
    2011
  • 资助金额:
    $ 24.7万
  • 项目类别:
Endocrine Network for Undergraduate Research and Carrier Development Opportunitie
本科生研究和载体发展机会内分泌网络
  • 批准号:
    8013376
  • 财政年份:
    2011
  • 资助金额:
    $ 24.7万
  • 项目类别:

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