FRS2-mediated Signals in Prostatic Tumorigenesis and Development

FRS2 介导的信号在前列腺肿瘤发生和发展中的作用

• 批准号: 7652704
• 负责人: FEN WANG
• 金额: $ 25.47万
• 依托单位: TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-06-01 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7652704
• 关键词: Ablation; Adaptor Signaling Protein; Alleles; American; Androgens; Animal Model; Animals; Attenuated; Basal Cell; Biochemical; Biological; Biological Assay; Cancer Diagnostics; Cancer Etiology; Cancer Patient; Cell Line; Cell physiology; Cells; Cessation of life; Data; Development; Dietary Component; Epithelial; Epithelial Cells; FGFR1 gene; FGFR2 gene; FRS2 gene; Fibroblast Growth Factor; Fibroblast Growth Factor Receptors; Future; Genetically Engineered Mouse; Growth; Health; Healthcare Systems; Homeostasis; In Vitro; Interruption; Life; Life Expectancy; Light; Link; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Methods; Molecular; Morphogenesis; Natural regeneration; Pathway interactions; Phosphotransferases; Play; Population; Prevention strategy; Preventive Intervention; Process; Prostate; Prostate Cancer therapy; Prostatic; Prostatic Neoplasms; Prostatic hypertrophy; Protein Isoforms; Protein Tyrosine Kinase; Quality of life; Receptor Signaling; Regulation; Role; Second Primary Cancers; Signal Pathway; Signal Transduction; Societies; Staging; Stem cells; Structure; Systems Analysis; Technology; Testing; Tissues; Tumor Escape; Tumorigenicity; base; cancer initiation; design; improved; in vivo; male; mouse model; neoplastic cell; novel; nutrition; precursor cell; prevent; public health relevance; receptor; tool; tumor; tumor initiation; tumor progression; tumorigenesis

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.

描述（由申请人提供）：多效性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、功能和体内平衡。 FGF 信号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点的衔接蛋白，在前列腺上皮细胞中被 FGFR1 和 FGFR2 激酶差异磷酸化。 FRS2？在发育中的前列腺中动态表达，这与前列腺分支形态发生、雄激素诱导的再生和肿瘤发生有关。该项目旨在检验以下假设：FRS2? 介导的信号的 FGFR 亚型特异性激活在前列腺上皮细胞发育和再生过程中的前体细胞增殖和分化中发挥重要作用，并且 FRS2? 介导的信号的异常激活有助于前列腺上皮细胞的增殖和分化。前列腺肿瘤发生，这是根据我们最近的发现制定的。工作重点将集中于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传导如何促进前列腺肿瘤的发生和进展。具体目的是表征FRS2的结构域？对于介导 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如何介导异常信号？有助于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？介导的信号在前列腺发育、组织稳态和肿瘤发生中的作用。了解 FGFR 信号在前列腺发育和肿瘤发生中的作用将为设计未来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最具诊断性的癌症，也是癌症死亡的第二大原因。与正常前列腺一样，早期前列腺癌依赖于雄激素。然而，在晚期，前列腺癌经常进展为不依赖雄激素并变成恶性。异常的细胞信号传导，包括由 FRS2? 介导的信号，通常伴随着恶性肿瘤的进展而被发现，这赋予了肿瘤细胞自主生长和侵袭的能力。该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。