MAMMARY GROWTH REGULATION: TRANSFORMING GROWTH FACTOR-B

乳房生长调节：转化生长因子-B

• 批准号: 3329512
• 负责人: CHARLES W DANIEL
• 金额: $ 17.67万
• 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 1995-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3329512
• 关键词: DNA replication; autoradiography; breast neoplasms; cell differentiation; cell growth regulation; complementary DNA; drug administration rate /duration; gel electrophoresis; growth inhibitors; histogenesis; hormone regulation /control mechanism; immunoprecipitation; laboratory mouse; laboratory rabbit; mammary epithelium; mammary gland; neoplastic growth; nucleic acid hybridization; nucleic acid probes; 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.

我们最近获得了可能的第一个证据 转化生长因子-β 的体内抑制作用 (TGF-Beta)，一种先前已鉴定出具有多种活性的肽 对培养细胞的影响，包括抑制增殖 文化中的各种上皮细胞。 使用小型塑料“Elvax”植入物 植入后能够持续局部释放 TGF-Beta 直接进入组织，我们发现 TGF-Beta 显着 抑制体内乳腺导管的生长。 效果是 完全可逆，并且在各个方面都模仿自然 腺体中生长调节的过程。 组织因子对细胞增殖的抑制被认为是 主要但知之甚少的稳态影响 正常组织的生长和维持。 这种负增长 监管对于癌症问题具有特殊意义；一个 恶性细胞的一个重要特征是它们的增殖能力 限制增长的监管影响的存在 正常细胞。 使用 mammary-Elvax 系统提供 增长调控的量化措施，我们建议扩大 我们的初步调查结果如下： 1. 表征 TGF-Beta 的生长调节，获取数据 时间进程、剂量依赖性、可逆性和其他 抑制的特点。 癌前和癌变的乳房 将研究组织以及几个正常生长阶段。 2. 生长抑制机制的研究 检查 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 结合特性。 3. TGF-β是自然生长的假设 将测试乳腺中的调节器。 其生产于 将直接测定体内和培养的乳腺细胞，并且 将测定TGF-β基因活性。 使用特定的 抗体从 Elvax 植入物局部释放， 中和将被确定。 TGF-β对细胞的影响 分化和上皮间质关系将是 调查了。