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）跨膜酪氨酸激酶来控制广泛的细胞过程，包括前列腺发育、功能和稳态。FGF信号传导轴的异常表达和激活通常与前列腺肿瘤的发生和进展相关。FRS2？是一种连接FGFR激酶与下游信号传导靶标的衔接蛋白，其在前列腺上皮细胞中被FGFR 1和FGFR 2激酶差异磷酸化。FRS2？在发育中的前列腺中动态表达，其与前列腺分支形态发生、雄激素诱导的再生和肿瘤发生相关。该项目是为了检验FGFR亚型特异性激活FRS 2？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FRS 2？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，细胞生物学和生物化学技术，以了解异常细胞信号传导如何有助于前列腺肿瘤的发生和发展。的具体目标是表征结构域的FRS 2？这是重要的介导FGFR信号;表征FRS 2在前列腺发育和组织稳态的作用;并调查如何异常信号介导的FRS 2？有助于前列腺肿瘤发生和肿瘤进展。目的是了解FGFR受体在底物水平的特异性信号和FRS 2？前列腺发育、组织稳态和肿瘤发生中的介导信号。了解FGFR信号在前列腺发育和肿瘤发生中的作用，将为未来设计预防和拦截前列腺癌发生和进展的新策略提供新的思路。该项目开发的动物模型不仅为进一步研究前列腺癌发生和进展中的FGFR信号提供了有用的工具，而且还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了有用的工具。公共卫生相关性：前列腺癌是美国男性中诊断率最高的癌症，也是癌症死亡的第二大原因。与正常前列腺一样，早期前列腺癌是雄激素依赖性的。然而，在晚期阶段，前列腺癌经常进展为雄激素非依赖性并变成恶性。异常细胞信号传导，包括FRS 2？介导的信号，通常伴随恶性进展而发现，其赋予肿瘤细胞自主生长和侵袭能力。本项目拟利用基因工程小鼠模型，采用体外生物化学和分子生物学方法，研究FRS 2？介导的信号在前列腺发育和肿瘤发生。

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.