The Ron Receptor in Mammary Gland Biology

描述（由申请人提供）：本研究的长期目标是确定受体酪氨酸激酶罗恩在乳腺生物学中的体内作用。事实上，关于罗恩在乳房中的功能还一无所知。然而，最近的研究表明，罗恩在大量的人类和猫科动物乳腺癌中过度表达和高度磷酸化。为了确定这种受体在体内的意义，我的实验室产生了有针对性的消融罗恩的酪氨酸激酶（TK）结构域的小鼠。对这些缺乏罗恩信号传导的小鼠的乳房发育的初步分析指出，受体酪氨酸激酶罗恩在乳腺生物学中的重要作用，但在很大程度上未得到重视。我们的初步研究表明，罗恩是所需的正常生长控制的乳腺发育和肿瘤发生过程中。本提案中的研究旨在更详细地研究这种相对未知的受体在乳腺发育和肿瘤发生中的作用。拟议的研究将采取初步措施，以确定潜在的机制，罗恩影响乳腺发育和肿瘤生物学在体内。我们的目标是严格探索以下特定假设：i）罗恩是乳腺发育中的有影响力的决定因素; ii）罗恩信号传导增强乳腺肿瘤发生和转移;以及iii）体内罗恩过表达导致乳腺转化。为了验证这些假设，我们提出了三个具体目标。目的I通过定位罗恩合成和罗恩作用的位点（间质、上皮或系统）来确定罗恩信号在乳腺发育中的作用。目的二是使用遗传学方法来检查在体内的影响，罗恩信号在致癌基因诱导的乳腺肿瘤的发病机制。为此，我们将分析罗恩信号和激活在乳腺肿瘤形成和转移扩散的作用。在目标III中，我们将重点了解罗恩过表达的作用，通过产生小鼠模型，模拟这种情况下观察到的人类癌症。总的来说，我们希望了解一种潜在的重要和未知的受体在乳腺生物学中的作用，并希望最终影响人类乳腺癌的治疗。

DESCRIPTION (provided by applicant): The long-term objective of my research is to define the in vivo role of the receptor tyrosine kinase Ron in mammary gland biology. Virtually nothing is known regarding the function of Ron in the breast. However, recent studies have shown that Ron is over-expressed and highly phosphorylated in a large number of human and feline breast cancers. In order to define the in vivo significance of this receptor, my laboratory generated mice with a targeted ablation of the tyrosine kinase (TK) domain of Ron. Preliminary analysis of breast development in these mice lacking Ron signaling has pointed to a major, and largely unappreciated, role for the receptor tyrosine kinase Ron in mammary gland biology. Our preliminary studies indicate that Ron is required for the normal growth control of the mammary gland both during development and during tumorigenesis. The studies in this proposal are aimed at examining in greater detail, the role of this relatively unknown receptor in mammary development and tumorigenesis. The proposed studies will take the initial steps toward defining the underlying mechanism by which Ron influences mammary gland development and tumor biology in vivo. Our goal is to rigorously explore the following specific hypotheses: i) Ron is an influential determinant in mammary gland development; ii) Ron signaling augments mammary gland tumorigenesis and metastasis; and iii) Ron over-expression in vivo leads to mammary transformation. In order to test these hypotheses, we have proposed three Specific Aims. Aim I is to define the contribution of Ron signaling in mammary gland development by localizing the sites of Ron synthesis and Ron action (stromal, epithelial or systemic). Aim II is to use a genetic approach to examine the in vivo impact of Ron signaling in the pathogenesis of oncogene-induced mammary gland tumors. For this aim we will analyze the role of Ron signaling and activation in mammary tumor formation and metastatic dissemination. In Aim III we will focus on understanding the role of Ron over-expression observed in human cancer by generating mouse models that mimic this conditions. In total, we hope to understand the role of a potentially important and unknown receptor in mammary biology with the hopes of ultimately impacting the treatment of human breast cancer.