ACTIVATION OF C SRC IN PANCREATIC CANCER BY FGFR 1B

描述(申请人的描述)：胰腺癌是最常见的 今天在医学上看到的致命肿瘤。在诊断出这种情况后， 只有不到4%的患者有望存活5年以上。理解 胰腺肿瘤细胞的弹性将需要分子的阐明 肿瘤形成过程中细胞生长和转化的调控机制。 该实验室和其他实验室正在进行的研究已经确定了增强的 成纤维细胞生长因子受体的选择性剪接异构体--成纤维细胞生长因子配体的出现 目的多肽中(FGFR-1β)诱导型一氧化氮合酶和总硝基酪氨酸。初步 研究表明，成纤维细胞生长因子激活的信号通过FGFR-1β促进 胰腺上皮细胞的生长和存活 化疗、放射治疗与过氧亚硝酸根(ONOO-)细胞凋亡 伴随着含有活化的c-Src出现的观察 磷酸化和硝化的酪氨酸残基。这些观察结果意味着 ONOO和成纤维细胞生长因子信号在肿瘤生长中相互依赖的关键作用 和转移行为。实验目标是在框架内设计的 假设临床上具有侵袭性的化疗和放射耐药 胰腺癌的特征是相互依存的结果 活性氮和配体激活的FGFR-1β向c-受体的信号转导 SRC。一个基本主题包括量化生产和有针对性的 ONOO调控成纤维细胞生长因子/FGFR-1β信号转导的分子反应 小路。特定分子试剂的可用性，已建立 技术，定义的人类和大鼠细胞种群，相关的啮齿动物模型， 临床标本可以通过基础机制研究来阐明 负责因果关系的分子事件 氧化应激与成纤维细胞生长因子生物学之间的关系。这些产品的详细特征 相互关系应为监测这一点提供诊断标准 毁灭性的疾病，并确定合理的策略来对抗胰腺 癌症。

DESCRIPTION (Applicant's Description): Pancreatic cancer is one of the most lethal tumors seen in medicine today. Following diagnosis of this condition, less than 4% of patients are expected to survive beyond 5 years. Understanding the resilience of pancreatic tumor cells will require elucidation of molecular mechanisms regulating cell growth anc transformation during neoplasia. Ongoing studies in this and other laboratories have identified the enhanced appearance of FGF ligands, an alteratively spliced isoform of the FGF receptor (FGFR-1beta) iNOS and total nitrotyrosine in target polypeptides. Preliminary studies demonstrate that FGF-activated signaling through FGFR-1beta promotes growth and the survival of pancreatic epithelial cells in response to chemotherapy, radiation treatment and peroxynitrite (ONOO-) apoptosis, an observation accompanied by the appearance of activated c-Src containing phosphorylated and nitrated tyrosine residues. These observations imply pivotal interdependent roles for ONOO and FGF signaling during tumor growth and metastatic behavior. Experimental aims are designed within the framework of the hypothesis that the clinically aggressive chemo- and radio-resistant features of pancreatic adenocarcinoma are the consequences of interdependent signaling of reactive nitrogen species and ligand-activated FGFR-1beta to c- Src. An underlying theme includes quantitating the production and targeted molecular responses to ONOO that modulate FGF/FGFR-1beta signal transduction pathways. The availability of specific molecular reagents, established techniques, defined human and rat cell populations, relevant rodent models, and clinical specimens permits fundamental mechanistic studies to elucidate molecular events responsible for the cause and effect interrelationship between oxidant stress and FGF biology. Detailed characteristics of these interrelationships should provide diagnostic criteria for monitoring this devastating disease and identify rational strategies to combat pancreatic cancer.