The Ron Receptor in Mammary Gland Biology

描述(申请人提供)：我研究的长期目标是确定受体酪氨酸激酶RON在乳腺生物学中的活体作用。关于RON在乳房中的作用，人们几乎一无所知。然而，最近的研究表明，在大量的人类和猫的乳腺癌中，RON过度表达和高度磷酸化。为了确定这种受体在体内的意义，我的实验室用靶向消融RON的酪氨酸激酶(TK)结构域的方法产生了小鼠。对这些缺乏RON信号的小鼠乳房发育的初步分析表明，受体酪氨酸激酶RON在乳腺生物学中起着重要的、但基本上未被认识的作用。我们的初步研究表明，RON在乳腺发育和肿瘤形成过程中都是正常生长控制所必需的。这项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步骤，以确定RON影响体内乳腺发育和肿瘤生物学的潜在机制。我们的目标是严格探索以下具体假设：i)RON是乳腺发育的重要决定因素；ii)RON信号增强乳腺肿瘤的发生和转移；iii)在体内过表达RON导致乳腺转化。为了检验这些假设，我们提出了三个具体目标。目的通过定位RON的合成和作用部位(间质、上皮性或全身性)，明确RON信号在乳腺发育中的作用。目的II用遗传学方法研究RON信号在癌基因诱导的乳腺肿瘤发病机制中的作用。为此，我们将分析RON信号和激活在乳腺肿瘤形成和转移转移中的作用。在目标III中，我们将通过建立模拟这种情况的小鼠模型，重点了解观察到的RON过度表达在人类癌症中的作用。总之，我们希望了解一个潜在的重要和未知的受体在乳腺生物学中的作用，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.