Stromal Periostin in Pancreatitis and Pancreas Cancer

胰腺炎和胰腺癌中的基质骨膜素

• 批准号: 8307010
• 负责人: Rosa F. Hwang
• 金额: $ 17.06万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-28 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8307010
• 关键词: Acinar Cell; Address; Aggressive course; Animal Model; Apoptosis; Biological; Biopsy Specimen; Blood; CXCL12 gene; CXCR4 gene; Cancer Center; Cell model; Cells; Cellular biology; Characteristics; Clinical; Collection; Conditioned Culture Media; Desmoplastic; Development; Diagnosis; Disease; Doctor of Medicine; Dose; Environment; Excision; Fibroblasts; Fibrosis; Fine needle aspiration biopsy; Goals; Human; In Vitro; Incidence; Inflammation; Injection of therapeutic agent; K-ras mouse model; Kinetics; Lesion; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediating; Mediator of activation protein; Mentors; Modeling; Molecular; Molecular Biology; Molecular Profiling; Mus; Neoplasm Metastasis; Nude Mice; Operative Surgical Procedures; Outcome; Pancreas; Pancreatic Adenocarcinoma; Pancreatitis; Play; Production; Progress Review Group; Radiation; Regulation; Research; Research Priority; Resistance; Risk Factors; Role; Sampling; Scientist; Signal Transduction; Staging; Stromal Neoplasm; Survival Rate; Testing; Therapeutic; Training; Transgenic Mice; United States National Institutes of Health; University of Texas M D Anderson Cancer Center; Work; autocrine; cancer cell; career; chemotherapy; chronic pancreatitis; effective therapy; genetic manipulation; human disease; improved; in vivo; innovation; intraepithelial; meetings; mortality; mouse model; mutant; neoplastic cell; novel; novel therapeutics; outcome forecast; pancreatic cancer cells; pancreatic neoplasm; periostin; public health relevance; response; skills; stellate cell; tumor; tumor progression

DESCRIPTION (provided by applicant): Pancreatic cancer has a dismal prognosis and conventional therapeutic approaches have had minimal impact to improve the course of this aggressive disease. Clearly, a better understanding of the molecular biology of pancreatic cancer is urgently needed to develop novel therapeutic strategies. The tumor-associated stroma is a hallmark characteristic of pancreatic cancer, yet little is known about its role in tumor progression. The same dense stroma is present in pancreatitis, which is a risk factor for pancreatic cancer. Our overall hypothesis is that a secreted factor produced by the stroma, periostin (PN), is important in pancreatitis and subsequent progression to pre-invasive and invasive pancreatic cancer. To test this hypothesis, we will use primary pancreatic stellate cells isolated from human pancreatic cancer-associated stroma in conjunction with state-of- the art animal models and mechanistic approaches to define the role of PN in the regulation of stromal fibroblasts, pancreatic cancer cells and tumor-stromal interactions. Our specific aims are: (1) To identify the effects of PN on pancreatic tumor progression and clinical outcome, (2) to determine the role of PN in the development of fibrosis in pancreatitis and in the progression from pancreatitis to pancreatic cancer, and (3) to characterize the association between PN and CXCL12. The candidate's immediate goals are to gain expertise in signaling mechanisms important in cancer and also to acquire new skills in mouse models of pancreatitis and pancreatic cancer. With the additional training, the candidate's long term goal is to develop an independent research career as a molecular and cell biologist focused on the role of the stroma in pancreatitis and its progression to pancreatic cancer. The candidate is well-prepared to achieve these goals by working with a mentor who is an internationally recognized expert in pancreatitis and pancreatic cancer. Moreover, he has successfully mentored two other K08 awardees in the past. In addition, the candidate will collaborate with well-established scientists who have substantial expertise in signal transduction and transgenic mouse models. Finally, the institutional environment at the University of Texas-M.D. Anderson Cancer Center provides an ideal setting to assure that the scientific and training goals of this application will be met. PUBLIC HEALTH RELEVANCE: Pancreatic cancer is a highly aggressive malignancy with essentially no effective treatment to date. This application focuses on the cells in the stroma, or tumor microenvironment, which are critical partners in cancer progression and metastasis but their precise mechanisms of action are poorly understood. A better understanding of the tumor-associated stroma may provide novel targets for treatment of pancreatic cancer.

描述（由申请人提供）：胰腺癌的预后令人沮丧，常规治疗方法对改善这种侵略性疾病的进程的影响很小。显然，迫切需要更好地了解胰腺癌的分子生物学，以开发新的治疗策略。肿瘤相关的基质是胰腺癌的标志性特征，但对其在肿瘤进展中的作用知之甚少。胰腺炎中存在相同的致密基质，这是胰腺癌的危险因素。我们的总体假设是，基质，骨膜蛋白（PN）产生的分泌因子在胰腺炎以及随后发展为侵入性和侵袭性胰腺癌的过程中很重要。为了检验这一假设，我们将使用从人胰腺癌相关的基质中分离出的原代胰腺星状细胞，并结合艺术动物模型和机械方法来定义PN在基质成纤维细胞，胰腺癌细胞和肿瘤细胞相互作用的调节中的作用。我们的具体目的是：（1）确定PN对胰腺肿瘤进展和临床结局的影响，（2）确定PN在胰腺炎中纤维化发展以及从胰腺炎发展到胰腺癌的发展，以及（3）以PN和CXCL12之间的关联来表征PN。候选人的直接目标是获得在癌症中重要的信号传导机制方面的专业知识，并在胰腺炎和胰腺癌的小鼠模型中获得新技能。通过额外的培训，候选人的长期目标是发展独立的研究职业，作为一名分子和细胞生物学家，专注于基质在胰腺炎中的作用及其发展为胰腺癌。候选人为实现这些目标做好了充分的准备，该目标是与一位胰腺炎和胰腺癌专家的导师合作。此外，他过去成功地指导了另外两名K08获奖者。此外，候选人将与具有信号转导和转基因小鼠模型具有丰富专业知识的良好科学家合作。最后，德克萨斯大学M.D大学的机构环境。安德森癌症中心（Anderson Cancer Center）提供了一个理想的环境，以确保将实现此应用程序的科学和培训目标。 公共卫生相关性：胰腺癌是一种高度侵略性的恶性肿瘤，迄今为止基本上没有有效的治疗方法。该应用的重点是基质中的细胞或肿瘤微环境，这些细胞是癌症进展和转移的关键伴侣，但其精确的作用机制知之甚少。更好地了解与肿瘤相关的基质可以为治疗胰腺癌提供新的靶标。