Discoidin Domain Receptors: Novel Players in Pancreatitis and Pancreatic Preneoplasia

盘状结构域受体：胰腺炎和胰腺癌前期的新参与者

• 批准号: 8811574
• 负责人: Howard C Crawford
• 金额: $ 21.39万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-12-10 至 2016-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8811574
• 关键词: Acinar Cell; Advanced Malignant Neoplasm; Area; Binding; Biochemical; Cancer Biology; Cells; Characteristics; Collagen; Data; Detection; Development; Diagnosis; Diagnostic; Disease; Duct (organ) structure; Ductal; Early Diagnosis; Early Intervention; Early treatment; Environment; Epithelial; Event; Family; Fibrosis; Genetic; Goals; In Vitro; Induced Mutation; Inflammation; Injury; Intervention; Investigation; Knockout Mice; Knowledge; Lead; Lesion; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediating; Metaplasia; Metaplastic; Methods; Modeling; Molecular; Mus; Mutation; Neoplasms; Oncogenic; Pancreas; Pancreatic Ductal Adenocarcinoma; Pancreatic Injury; Pancreatitis; Pathogenesis; Pharmaceutical Preparations; Play; Premalignant; Process; Proteins; Receptor Protein-Tyrosine Kinases; Regulation; Research; Risk Factors; Role; Scientist; Signal Pathway; Signal Transduction; Staging; Stimulus; Testing; Tissues; Work; anticancer research; base; cancer diagnosis; cancer therapy; chronic pancreatitis; discoidin receptor; experience; in vivo; in vivo Model; neoplastic; novel; novel marker; novel strategies; pancreatic neoplasm; progenitor; programs; public health relevance; receptor; receptor expression; response; therapeutic target; tool; transdifferentiation

DESCRIPTION (provided by applicant): The goal of this R21 application is to pursue a novel area of investigation in pancreatic cancer development, and apply this knowledge for early disease detection and treatment. Pancreatic Ductal Adenocarcinoma (PDAC) is a highly lethal form of cancer that is characterized by a strong fibrotic response, which promotes malignancy. Pancreatic inflammation (pancreatitis) and the ensuing fibrotic response cause the acinar cells to undergo a metaplastic event in which the acinar cells transdifferentiate into duct-like cells wih progenitor-like characteristics, a process known as Acinar-to-Ductal Metaplasia (ADM). Current concepts indicate that ADM constitute the early pathological lesion that eventually progresses into PDAC. ADM proceeds within the context of a pro-fibrotic collagen-rich matrix, which is a key feature of PDAC and chronic pancreatitis, a risk factor for PDAC development. Therefore, the interactions of the acinar cells with the underlying collagen matrix are likely to play a pivotal rle in the activation of the transdifferentiation programs that lead to ADM lesions and eventually to PDAC development. However, how acinar cells respond to the collagen matrix during formation of ADM lesions remains ill defined. New preliminary evidence suggests a role for the Discoidin Domain Receptors (DDRs), a unique set of receptor tyrosine kinases that signal in response to collagen and thus represent logical candidates for mediating the morphogenetic programs of acinar cells during ADM. However, the expression and functional contribution of DDRs in ADM formation and pancreatitis have not been investigated. Because DDRs mediate collagen-initiated signaling and, as RTKs, are amenable to drug intervention, we propose the novel hypothesis that DDRs mediate the reprograming of acinar cells within the collagen microenvironment that contribute to ADM formation during pancreatic injury and early neoplastic development. To test this hypothesis, we propose the two Specific Aims: 1) To investigate the contribution of DDRs to acinar-to-ductal metaplasia (ADM) in acinar explants, and 2) To investigate the expression and role of DDRs in pancreatitis. To accomplish these Aims we will utilize a variety of relevant in vitro and in vivo models that recapitulate the morphogenetic program of ADM including acinar explants and pancreatitis models, and exploit the availability of mice with genetic disruption of DDR expression and various tools to target DDR activity. We expect that the results of these novel studies will pave the way for a new scientific direction in PDAC research, which may lead to the development of new approaches in pancreatic cancer diagnosis and treatment. Hence, the studies proposed in this application are in line with the R21 goals to promote the early and conceptual stages of research efforts on novel scientific ideas that have the potential to substantially advance cancer research.

描述（由申请人提供）：该R21申请的目的是追求胰腺癌发育中的新型调查领域，并将这些知识应用于早期疾病检测和治疗。胰腺导管腺癌（PDAC）是一种高度致命的癌症形式，其特征在于强烈的纤维化反应，可促进恶性肿瘤。胰腺炎症（胰腺炎）和随后的纤维化反应会导致腺泡细胞经历过化的事件，其中腺泡细胞将腺细胞转分化成具有类似祖细胞的管道样细胞，这一过程被称为刺激性抗糖膜 - 导管 - 导管 - 导向性脱氧型甲虫（ADM）。当前的概念表明，ADM构成了最终发展为PDAC的早期病理病变。 ADM在促纤维胶原蛋白基质的背景下进行，这是PDAC和慢性胰腺炎的关键特征，PDAC和慢性胰腺炎是PDAC发育的危险因素。因此，腺泡细胞与基础胶原基质的相互作用可能在激活转分化程序的激活中起着关键性RLE，从而导致ADM病变并最终导致PDAC发育。然而，在ADM病变形成期间，腺泡细胞如何对胶原基质反应。新的初步证据表明，盘状蛋白结构域受体（DDRS）的作用是一组独特的受体酪氨酸激酶，该激酶对胶原蛋白发出信号，因此代表了ADM期间介导腺细胞形态发生程序的逻辑候选者。但是，尚未研究DDR在ADM组和胰腺炎中的表达和功能贡献。由于DDR介导了胶原蛋白引发的信号传导，并且作为RTK，我们可以接受药物干预，因此我们提出了一种新的假设，即DDRS介导胶原微环境中腺泡细胞的重编程，从而在胰腺损伤期间有助于ADM形成，并在胰腺损伤和早期肿瘤发育过程中进行ADM形成。为了检验这一假设，我们提出了两个具体目的：1）研究DDR对腺泡外植体中DDR的贡献（ADM），以及2）研究DDR在胰腺炎中的表达和作用。为了实现这些目标，我们将利用各种相关的体外和体内模型，这些模型概括了ADM的形态发生程序，包括腺泡外植体和胰腺炎模型，并利用具有DDR表达的基因破坏和各种工具的小鼠的可用性来靶向DDR活动。我们预计这些新研究的结果将为PDAC研究的新科学方向铺平道路，这可能导致胰腺癌诊断和治疗的新方法发展。因此，本应用程序中提出的研究符合R21目标，以促进对新型科学思想的研究工作的早期和概念阶段，这些阶段有可能大大提高癌症研究。