FRS2-mediated Signals in Prostatic Tumorigenesis and Development

描述(申请人提供)：多效性成纤维细胞生长因子通过激活四种高度同源的成纤维细胞生长因子受体(FGFR)跨膜酪氨酸激酶，控制广泛的细胞过程，包括前列腺发育、功能和动态平衡。成纤维细胞生长因子信号轴的异常表达和激活常被发现与前列腺癌的发生发展有关。FRS2？是一种连接FGFR激酶和下游信号靶点的接头蛋白，它被前列腺上皮细胞中的FGFR1和FGFR2激酶差异磷酸化。FRS2？在发育中的前列腺中动态表达，与前列腺分支形态发生、雄激素诱导的再生和肿瘤的发生有关。本项目旨在验证FGFR异构体特异性激活FRS2？介导的信号在前列腺上皮细胞发育和再生过程中调节前体细胞增殖和分化中的重要作用，以及FRS2？介导的信号异常激活与前列腺癌的发生有关的假说，这是根据我们最近的发现提出的。重点是利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在前列腺癌的发生和发展中起作用。具体目的是描述FRS2？的结构域。FRS2在前列腺发育和组织动态平衡中的作用，以及研究FRS2是如何介导异常信号的？有助于前列腺癌的发生和肿瘤的进展。其目的是了解FGFR如何在底物水平引起受体特异性信号，以及FRS2？介导的信号在前列腺发育、组织内稳态和肿瘤发生中的作用。了解FGFR信号在前列腺发育和肿瘤发生中的作用，将为设计新的预防和阻断前列腺癌发生和发展的新策略提供新的线索。该项目开发的动物模型不仅将为进一步研究前列腺癌发生和发展中的FGFR信号提供有用的工具，还将为评估营养和活性膳食成分在预防、干预和阻断前列腺癌进展方面的作用提供有用的工具。公共卫生相关性：前列腺癌是最具诊断性的癌症，也是美国男性癌症死亡的第二大原因。像正常的前列腺癌一样，早期前列腺癌依赖于雄激素。然而，在晚期，前列腺癌经常进展到雄激素非依赖性和恶性。异常的细胞信号，包括FRS2？介导的信号，经常伴随着肿瘤细胞的恶性进展，赋予肿瘤细胞自主生长和侵袭的能力。本项目旨在利用基因工程小鼠模型以及体外生化和分子生物学方法来研究FRS2？介导的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.