HORMONAL REGULATION OF THE MAMMARY IGF SYSTEM

乳房 IGF 系统的荷尔蒙调节

• 批准号: 2149390
• 负责人: CHARLES W DANIEL
• 金额: $ 17.83万
• 依托单位: UNIVERSITY OF CALIFORNIA SANTA CRUZ
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-09-30 至 1998-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2149390
• 关键词: binding proteins; cell growth regulation; estrogens; gene expression; hormone receptor; hormone regulation /control mechanism; implant; insulinlike growth factor; laboratory mouse; mammary gland; northern blottings; progesterone

The endocrine mammogens estrogen and progesterone drive not only normal but also neoplastic mammary growth. Underlying mechanisms are poorly understood but no doubt involve the regulation of tissue intermediaries such as Insulin-like Growth Factors (IGFs) which are potent mitogens for normal mammary cells in vitro and have been implicated in the uncontrolled, neoplastic growth of these cells. Using slow-release plastic implants to treat small regions of the mouse mammary gland in situ, we recently demonstrated localized synergy of IGF with estrogen to stimulate ductal growth. At the doses used, neither estrogen or IGF-I alone stimulated the gland. This effect, along with the presence of abundant IGF-I message in the gland, is strong evidence that IGF-I is a normal, locally-acting ductal mammogen. We now propose to investigate local hormonal regulation of the IGF system and have developed a completely novel in vivo research system to do so. Slow-release implants containing antiestrogen or antiprogesterone are used to ablate cognate receptor action; localized disruption of steroid- dependent gene expression is detectable using standard methods such as Northern hybridization analysis. The capacity to relate steroid action to growth factor regulation is crucial to understanding glandular regulation in normal and pathological circumstances. Indeed, this single point is the focus of the RFA to which this proposal responds. The clearcut capability of our system to link steroid/growth factor modulation in a straightforward, unambiguous manner is described in preliminary studies. This system therefore promises direct answers to many questions concerning estrogen and progesterone regulation of the IGF system within the normal, preneoplastic and neoplastic gland. This new approach will be used to investigate estrogen and progesterone regulation of IGF-I, IGF-II, IGF type 1 and type 2 receptors, as well as certain IGF binding proteins in vivo. It is expected that the details of hormonal regulation of paracrine and negative feedback regulation of IGF action will come into focus. Growth-regulatory functions for specific binding proteins, inferred from the above experiments will be further defined by implanting mutant forms of IGI to perturb normal activity and unmask local actions. Our ability to relate gene expression to well- defined, biologically relevant end points within the gland (ductal growth versus inhibition), means that strong inferences concerning the functional importance of hormonal regulation of the IGF system will be forthcoming.

内分泌的催乳激素雌激素和孕激素不仅驱动正常 而且还有肿瘤性乳房生长。潜在的机制很差 这是可以理解的，但毫无疑问， 例如胰岛素样生长因子（IGF），其是有效的有丝分裂原， 正常乳腺细胞在体外，并已牵连在 不受控制的肿瘤生长。使用缓释塑料 植入物原位治疗小鼠乳腺的小区域，我们 最近证明了IGF与雌激素的局部协同作用， 导管生长在使用的剂量下，无论是雌激素还是IGF-I， 刺激腺体这种效应，沿着丰富的 IGF-I在腺体中的信使，是IGF-I正常的有力证据， 局部作用的乳腺导管激素 我们现在建议研究IGF系统的局部激素调节 并开发了一种全新的体内研究系统来实现这一点。 使用含有抗雌激素或抗孕酮的缓释植入剂 消除同源受体作用;类固醇的局部破坏- 依赖性基因表达可以使用标准方法检测，例如 北方杂交分析。将类固醇作用与 生长因子调节对于了解腺体调节是至关重要的 在正常和病态的情况下。其实，这一点， 这是本提案所回应的RFA的重点。明确的能力 我们的系统将类固醇/生长因子调节与 在初步研究中描述了直接、明确的方式。 因此，这一系统有望直接回答有关 雌激素和孕激素调节IGF系统内正常， 肿瘤前和肿瘤腺。 这种新方法将用于研究雌激素和孕激素 调节IGF-I、IGF-II、IGF 1型和2型受体，以及 体内某些IGF结合蛋白。预计， 旁分泌激素调节与IGF负反馈调节 行动将成为焦点。生长调节功能， 结合蛋白，从上述实验推断，将进一步 通过植入IGI的突变形式来扰乱正常活动， 揭露本地行为。我们将基因表达与- 腺体内定义的生物学相关终点（导管生长 相对于抑制），意味着关于功能的强推论 IGF系统的激素调节的重要性即将到来。