MAMMARY REGULATION BY TRANSFORMING GROWTH FACTOR-BETA

通过改变生长因子-β 来调节乳房

• 批准号: 3188277
• 负责人: CHARLES W DANIEL
• 金额: $ 13.89万
• 依托单位: UNIVERSITY OF CALIFORNIA SANTA CRUZ
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-09-30 至 1990-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3188277
• 关键词: autoradiography; breast neoplasms; cell differentiation; cell growth regulation; complementary DNA; drug administration rate /duration; gel electrophoresis; growth inhibitors; histogenesis; hormone regulation /control mechanism; immunoprecipitation; mammary epithelium; mammary gland; neoplastic growth; preneoplastic state; radioimmunoassay; radiotracer; tissue /cell culture; transforming growth factors

We have recently obtained the first evidence for a possible inhibitory role in vivo for Transforming Growth Factor-Beta (TGF-Beta), a peptide previously identified with a variety of effects on cultured cells, including inhibition of proliferation of various epithelia in culture. Using small plastic "Elvax" implants capable of sustained, local release of TGF-Beta when implanted directly into tissues, we found that TGF-Beta dramatically inhibited the growth of mammary ducts in vivo. The effect was fully reversible and appeared in all respects to mimic the natural process of growth regulation in the gland. Inhibition of cell proliferation by tissue factors in thought to be a major, though poorly understood homeostatic influence operating in normal tissue growth and maintenance. This negative growth regulation is of special significance to the cancer problem; a critical feature of malignant cells is their ability to proliferate in the presence of regulative influences that restrain the growth of normal cells. Using the mammary-Elvax system to provide a quantitative measure of growth regulation, we propose to expand our preliminary findings as follows: 1. Characterize growth regulation by TGF-Beta, obtaining data on the time course, dose-dependency, reversibility, and other features of inhibition. Precancerous and cancerous mammary tissues will be studied as well as several normal growth stages. 2. Mechanisms of growth inhibition will be investigated by examining interactions of TGF-Beta with other growth factors and hormones, and by determining receptor localization and ligand binding characteristics. 3. The hypothesis that TGF-Beta is a naturally occurring growth regulator in the mammary gland will be tested. Its production in vivo and in cultured mammary cells will be directly assayed, and TGF-Beta gene activity will be determined. Using specific antibody released locally from Elvax implants, the effects of neutralization will be determined. Influences of TGF-Beta on cell differentiation and on epithelial-stroma relations will be investigated.

我们最近获得了第一个证据， 转化生长因子-β体内抑制作用 （TGF-β），一种先前与多种肿瘤相关的肽， 对培养细胞的影响，包括抑制 各种上皮细胞培养。 使用小型塑料“Elvax”植入物 植入时能够持续局部释放TGF-β 我们发现TGF-β显著地 抑制乳腺导管的生长。 效果 完全可逆，在各方面都模仿了自然的 腺体的生长调节过程。 组织因子对细胞增殖的抑制被认为是 主要的，虽然知之甚少的稳态影响操作 正常组织的生长和维持。 这种负增长 监管对癌症问题具有特殊意义; 恶性细胞的一个重要特征是它们在细胞内增殖的能力。 存在抑制生长的调节性影响， 正常细胞 使用乳房-Elvax系统提供 增长调节的定量措施，我们建议扩大 我们的初步调查结果如下： 1. 通过TGF-β表征生长调节，获得数据 时间进程、剂量依赖性、可逆性和其他 抑制的特征。 乳腺癌前和癌 将研究组织以及几个正常生长阶段。 2. 将通过以下方法研究生长抑制机制： 研究TGF-β与其他生长因子的相互作用 和激素，并通过确定受体定位和配体 绑定特性 3. 假设TGF-β是一种自然发生的生长 将测试乳腺中的调节剂。 出示时 将直接测定体内和培养的乳腺细胞， 将确定TGF-β基因活性。 使用特定 Elvax植入物局部释放的抗体， 将确定中和。 TGF-β对细胞的影响 分化和上皮间质的关系将是 研究了