FRS2-mediated Signals in Prostatic Tumorigenesis and Development

描述（由申请人提供）：多效成纤维细胞生长因子（FGF）通过激活四种高度同源的FGF受体（FGFR）跨膜酪氨酸激酶，控制广泛的细胞过程，包括前列腺发育、功能和稳态。FGF信号轴的异常表达和激活常被发现与前列腺肿瘤的发生和进展有关。FRS2吗?是一种连接FGFR激酶与下游信号靶点的衔接蛋白，在前列腺上皮细胞中被FGFR1和FGFR2激酶不同地磷酸化。FRS2吗?在发育中的前列腺中动态表达，与前列腺分支形态发生、雄激素诱导再生和肿瘤发生有关。该项目是为了验证FGFR亚型特异性激活FRS2？-介导的信号在调节前列腺上皮细胞发育和再生过程中前体细胞的增殖和分化以及FRS2？-介导的信号有助于前列腺肿瘤的发生，这是根据我们最近的发现制定的。努力将集中在使用基因工程小鼠以及分子生物学，细胞生物学和生化技术来了解异常细胞信号如何促进前列腺肿瘤的发生和发展。具体目的是表征FRS2的结构域。对介导FGFR信号很重要；表征FRS2在前列腺发育和组织稳态中的作用；并研究FRS2介导的异常信号是如何发生的？促进前列腺肿瘤发生和肿瘤进展。目的是了解FGFR如何在底物水平引发受体特异性信号以及FRS2的作用。-介导信号在前列腺发育、组织稳态和肿瘤发生中的作用。了解FGFR信号在前列腺发展和肿瘤发生中的作用，将为未来设计预防和阻断前列腺癌发生和发展的新策略提供新的思路。该项目开发的动物模型不仅将为进一步研究FGFR信号在前列腺癌发生和进展中的作用提供有用的工具，而且还将为评估营养和活性饮食成分在预防、干预和中断前列腺肿瘤进展中的作用提供有用的工具。公共卫生相关性：前列腺癌是诊断性最高的癌症，也是美国男性癌症死亡的第二大原因。与正常前列腺一样，早期前列腺癌依赖于雄激素。然而，在晚期，前列腺癌经常发展为雄激素不依赖型并成为恶性肿瘤。异常细胞信号，包括由FRS2介导的信号。它通常伴随着恶性肿瘤的进展，赋予肿瘤细胞自主生长和侵袭能力。本项目拟采用基因工程小鼠模型及体外生化和分子生物学方法研究FRS2？-介导信号在前列腺发育和肿瘤发生中的作用。

DESCRIPTION (provided by applicant): The pleiotropic fibroblast growth factors (FGF) control a broad spectrum of cellular processes, including prostate development, function, and homeostasis, by activating the four highly homologous FGF receptor (FGFR) transmembrane tyrosine kinases. Aberrant expression and activation of the FGF signaling axis are often found associated with prostatic tumor development and progression. FRS2? is an adaptor protein linking the FGFR kinases to downstream signaling targets, which is differentially phosphorylated by the FGFR1 and FGFR2 kinases in prostate epithelial cells. FRS2? is dynamically expressed in developing prostates, which is associated with prostatic branching morphogenesis, androgen-induced regeneration, and tumorigenesis. The project is to test the hypothesis that FGFR isoform-specific activation of FRS2?-mediated signals play important roles in regulating proliferation and differentiation of precursor cells for prostatic epithelial cells during development and regeneration, and aberrant activation of FRS2?-mediated signaling contributes to prostatic tumorigenesis, which was formulated based on our recent findings. Efforts will be focused on using genetically engineered mouse as well as molecular biological, cell biological, and biochemical technologies to understand how aberrant cell signaling contributes to prostate tumor initiation and progression. The specific aims are to characterize the structural domain of FRS2? that are important for mediating FGFR signals; to characterize the role of FRS2 in prostatic development and tissue homeostasis; and to investigate how aberrant signals mediated by FRS2? contribute to prostatic tumorigenesis and tumor progression. The objective is to understand how FGFR elicits receptor specific signals at the substrate level and the roles of FRS2?-mediated signals in prostatic development, tissue homeostasis, and tumorigenesis. Understanding the role of FGFR signals in prostatic development and tumorigenesis will shed new light on designing new strategies for prevention and interception of prostate cancer initiation and progression in the future. Animal models developed in the project will provide a useful tool not only for further studying FGFR signals in prostate cancer initiation and progression, but also for assessing the role of nutrition and active dietary components on prevention, intervention, and interruption on prostate tumor progression. PUBLIC HEALTH RELEVANCE: Prostate cancer is the most diagnostic cancer and the second leading cause of cancer death in American males. Like normal prostates, prostate cancer at early stages is androgen dependent. Yet, at late stages, prostate cancer frequently progresses to androgen independent and becomes malignant. Aberrant cell signaling, including signals mediated by FRS2?, often found accompanying the progression to malignancy, which confers autonomous growth and invasion capability to tumor cells. This project is to use genetically engineered mouse models and in vitro biochemical and molecular biological methods to study the roles of FRS2?-mediated signals in prostate development and tumorigenesis.