IGF and IGF Receptor Function in Mammary Development

IGF 和 IGF 受体在乳腺发育中的功能

• 批准号: 6846630
• 负责人: Teresa L Wood
• 金额: $ 26.87万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-03-01 至 2006-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6846630
• 关键词: biological signal transduction; breast neoplasms; cell cycle; cell differentiation; developmental genetics; epidermal growth factor; fibroblast growth factor; gene expression; genetically modified animals; genotype; growth factor receptors; hormone regulation /control mechanism; insulinlike growth factor; laboratory mouse; mammary epithelium; mammary gland; northern blottings; organ culture; progesterone; protein structure function; terminal nick end labeling; transforming growth factors; western blottings

The research plan outlined in this proposal will elucidate the mechanisms by which the insulin-like growth factors, IGF-I and IGF-II, and their primary signaling receptor, the IGF type I receptor (IGF-IR) mediate growth and differentiation of cells in the mammary gland. The goal of the proposal is to test the hypotheses that: 1) the IGFs and IGF-IR are essential for mammary epithelial proliferation and for epithelial-stromal signaling, and 2) IGF-I and IGF-II have differential functions in mediating mammary gland growth and differentiation. Experiments in specific aim one utilize a mammary gland culture system to determine whether IGF signaling regulates cell cycle progression in the mammary gland by regulating expression and activation of both the G1 and G2 checkpoint complexes. These experiments also will elucidate the mechanisms for IGF/EGF interactions in mediating cell cycle progression during mammary development. In the second specific aim, a genetic approach will be used to test the role of IGF-IR signaling in EGF or TGF- mediated growth of mammary glands in vitro and in vivo. Experiments in aim two also will address the role of the IGF-IR in epithelial-stromal signaling in mammary development. In aim three of the research plan, we will utilize additional genetic approaches to test whether IGF-I and IGF-II function differentially in mammary development. These experiments will include studies to determine whether IGF-II expression is directly regulated by progesterone in the mammary gland. The experimental data generated will have a significant impact on our understanding of IGF and IGF receptor function in normal development of this tissue. The IGFs and IGF-IR are among the increasing numbers of genes with proposed roles in both normal breast development and breast cancer, thus, results of these experiments also will provide a basis for understanding mechanisms of IGF action in breast cancer.

这项建议中概述的研究计划将阐明胰岛素样生长因子IGF-I和IGF-II及其主要信号受体I型受体(IGF-IR)介导乳腺细胞生长和分化的机制。该提案的目的是验证以下假设：1)IGFS和IGF-IR对乳腺上皮细胞增殖和上皮-间质信号转导是必不可少的；2)IGF-I和IGF-II在调节乳腺生长和分化方面具有不同的功能。实验一利用乳腺培养系统来确定IGF信号是否通过调节G1和G2检查点复合体的表达和激活来调节乳腺细胞周期的进展。这些实验还将阐明IGF/EGF相互作用在调节乳腺发育过程中细胞周期进展的机制。在第二个特定目标中，将使用遗传学方法来测试IGF-IR信号在体外和体内EGF或转化生长因子介导的乳腺生长中的作用。目标二的实验还将探讨IGF-IR在乳腺发育中上皮-间质信号转导中的作用。在研究计划的第三个目标中，我们将利用其他遗传方法来测试IGF-I和IGF-II在乳房发育中的不同功能。这些实验将包括确定IGF-II在乳腺中的表达是否直接受黄体酮调节的研究。产生的实验数据将对我们理解IGF及其受体在该组织正常发育中的作用产生重大影响。IGFS和IGF-IR是越来越多的基因中被认为在正常乳腺发育和乳腺癌中发挥作用的基因之一，因此，这些实验结果也将为理解IGF在乳腺癌中的作用机制提供基础。