MAMMARY GROWTH REGULATION: TRANSFORMING GROWTH FACTOR-B

乳房生长调节：转化生长因子-B

• 批准号: 2200678
• 负责人: CHARLES W DANIEL
• 金额: $ 18.69万
• 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/2200678
• 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; iodine; laboratory mouse; laboratory rabbit; mammary epithelium; mammary gland; neoplastic growth; nucleic acid hybridization; nucleic acid probes; preneoplastic state; radioimmunoassay; radionuclides; 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，证明 转化生长因子-β在体内的抑制作用 (转化生长因子-β)，一种先前被鉴定为多种 对培养细胞的影响，包括抑制细胞增殖 培养中的各种上皮细胞。使用小型塑料“Elvax”植入物 植入后能够持续、局部释放转化生长因子-β 直接进入组织，我们发现转化生长因子β戏剧性地 抑制体内乳腺导管的生长。其效果是 完全可逆，在各个方面似乎都模仿了自然 腺体的生长调节过程。 组织因子抑制细胞增殖被认为是一种 主要的，尽管鲜为人知的动态平衡影响运作 在正常的组织生长和维持中。这种负增长 监管对癌症问题具有特殊意义；a 恶性细胞的关键特征是它们能够在 存在着抑制增长的调节影响 正常细胞。使用乳房-Elvax系统提供 增长调控的量化措施，我们建议扩大 我们的初步研究结果如下： 1.研究转化生长因子-β对生长的调控作用，获取数据 关于时间进程、剂量依赖性、可逆性等 抑制的特征。癌前病变和癌前病变 将对组织以及几个正常生长阶段进行研究。 2.生长抑制的机制将通过以下方式进行研究 检测转化生长因子-β与其他生长因子的相互作用 和激素，并通过确定受体的定位和配体 约束性特征。 3.假设转化生长因子-β是一种自然生成的生长 将对乳腺中的调节器进行测试。它的生产在 将直接检测体内和培养的乳腺细胞，以及 将测定转化生长因子-β基因活性。使用特定的 Elvax植入物局部释放的抗体，对 中和将被确定。转化生长因子-β对细胞的影响 分化和上皮-间质关系将是 调查过了。