Notch signaling in initiation and progression of pancreatic cancer

Notch信号传导在胰腺癌的发生和进展中

基本信息

批准号：
7406050
负责人：
Lewis C Murtaugh
金额：
$ 14.95万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-04-12 至 2010-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7406050
关键词：
Acinar Cell Address Adenocarcinoma Cell Adult Biology Cell Line Cells Competence Development Diagnosis Disease Drug Delivery Systems Dysplasia Embryo Exhibits Figs - dietary Future Gene Targeting Genes Genetic Growth Human In Vitro K-ras Oncogene LY411575 Lesion Light Maintenance Malignant Neoplasms Malignant neoplasm of pancreas Metaplasia Molecular Mus NIH Program Announcements Neoplasms Notch Signaling Pathway Oncogenic Organogenesis Outcome Pancreas Pancreatic Ductal Adenocarcinoma Pancreatic Intraepithelial Neoplasia Pathway interactions Physiological Pilot Projects Premalignant Process Public Health Reagent Research Role Signal Transduction Site Stem cells Testing Therapeutic Transgenic Mice Up-Regulation Work base cancer cell cell type chemotherapeutic agent clinically relevant human disease in vivo inhibitor/antagonist loss of function mouse model neoplastic cell notch protein pancreatic neoplasm pancreatic tumorigenesis pre-clinical progenitor programs stem tumor initiation tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): The overall hypothesis that guides our research is that molecular regulators of pancreatic organogenesis, originally deployed in the embryo, remain relevant to adult disease processes. Among these regulators is the Notch signaling pathway, which the PI has previously studied in an embryonic context. Based on a recent NCI Program Announcement, seeking proposals for pilot studies in pancreatic cancer (PA-06- 303), we have begun to investigate the role of Notch signaling in pancreatic cancer. Notch acts to inhibit differentiation in the developing pancreas; although Notch pathway activation has been detected in human pancreatic cancer, its role there has not yet been determined. Notch activation is also observed in the precancerous lesions that form in a mouse model of this disease, driven by activation of the K-ras oncogene. Our preliminary evidence indicates that Notch activation dramatically sensitizes pancreatic progenitor cells to K-ras-induced dysplasia, and we hypothesize that Notch signaling in the adult drives dedifferentiation to a progenitor-like state that is similarly susceptible to K-ras. Here, we propose two Specific Aims to study the role of Notch signaling in initiation and progression of pancreatic cancer. (1) We will activate K-ras and/or Notch signaling in differentiated cells of the adult mouse pancreas, and determine whether the pathways synergistically promote the formation of precancerous lesions. (2) We will determine the requirement for continued Notch signaling in initiation, progression and maintenance of pancreatic cancer, applying independent loss-of-function approaches to intact mice as well as cultured human pancreatic cancer cells. In addition to guiding future mechanistic studies of Notch and K-ras synergy, we anticipate that the outcome of this work will be of considerable clinical relevance, given that the Notch pathway is a potential target for pharmacological inhibition in humans. Public Health Relevance: This proposal seeks to implicate or exclude the Notch signaling pathway as a potential drug target in pancreatic cancer. In addition, it will shed new light on the cellular and molecular origins of this deadly human disease. The research described in this application is 100% relevant to pancreatic cancer.

描述（由申请人提供）：指导我们研究的总体假设是，最初在胚胎中部署的胰腺器官发生的分子调节剂仍然与成人疾病过程相关。这些调节因子中包括 Notch 信号通路，PI 之前已在胚胎环境中对其进行了研究。根据最近的 NCI 计划公告，寻求胰腺癌试点研究提案 (PA-06-303)，我们已开始研究 Notch 信号传导在胰腺癌中的作用。 Notch 的作用是抑制发育中的胰腺的分化；尽管已在人类胰腺癌中检测到Notch通路激活，但其作用尚未确定。在这种疾病的小鼠模型中形成的癌前病变中也观察到了缺口激活，这是由 K-ras 癌基因激活驱动的。我们的初步证据表明，Notch 激活使胰腺祖细胞对 K-ras 诱导的发育不良显着敏感，并且我们假设成人中的 Notch 信号传导驱动去分化至类似祖细胞的状态，该状态同样对 K-ras 敏感。在这里，我们提出了两个具体目标来研究 Notch 信号在胰腺癌发生和进展中的作用。 (1)我们将激活成年小鼠胰腺分化细胞中的K-ras和/或Notch信号，并确定这些通路是否协同促进癌前病变的形成。 (2) 我们将通过对完整小鼠以及培养的人类胰腺癌细胞应用独立的功能丧失方法来确定胰腺癌的发生、进展和维持中持续的Notch信号传导的需要。除了指导未来 Notch 和 K-ras 协同作用的机制研究之外，我们预计这项工作的结果将具有相当大的临床意义，因为 Notch 途径是人类药理抑制的潜在靶点。公共健康相关性：该提案旨在暗示或排除 Notch 信号通路作为胰腺癌的潜在药物靶点。此外，它将为这种致命的人类疾病的细胞和分子起源提供新的线索。本申请中描述的研究与胰腺癌 100% 相关。