Discoidin Domain Receptors: Novel Players in Pancreatitis and Pancreatic Preneoplasia

描述（由申请人提供）：该R21申请的目标是在胰腺癌发展中探索一个新的研究领域，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，这会促进恶性肿瘤的发生。胰腺炎症（胰腺炎）和随后的纤维化反应导致腺泡细胞经历化生事件，其中腺泡细胞转分化成具有祖细胞样特征的导管样细胞，该过程称为腺泡至导管化生（ADM）。目前的概念表明，ADM构成的早期病理损害，最终进展为PDAC。ADM在促纤维化的富含胶原的基质中进行，这是PDAC和慢性胰腺炎的关键特征，是PDAC发展的风险因素。因此，腺泡细胞与底层胶原基质的相互作用可能在导致ADM损伤并最终导致PDAC发展的转分化程序的激活中起关键作用。然而，腺泡细胞在ADM病变形成过程中对胶原基质的反应仍不清楚。新的初步证据表明，盘状结构域受体（DDRs）的作用，一组独特的受体酪氨酸激酶，在胶原蛋白的信号，从而代表逻辑候选人介导的腺泡细胞的形态发生程序在ADM。然而，在ADM形成和胰腺炎的DDRs的表达和功能的贡献还没有被调查。由于DDRs介导胶原启动的信号传导，并且作为RTK，易于药物干预，我们提出了新的假设，即DDRs介导胶原微环境内腺泡细胞的重编程，这有助于胰腺损伤和早期肿瘤发展期间ADM的形成。为了验证这一假设，我们提出了两个特定的目的：1）研究DDRs对腺泡外植体中腺泡-导管化生（ADM）的贡献，2）研究DDRs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，概括ADM的形态发生程序，包括腺泡外植体和胰腺炎模型，并利用DDR表达遗传破坏的小鼠和靶向DDR活性的各种工具的可用性。我们希望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新方法的发展。因此，本申请中提出的研究符合R21目标，即促进有可能大幅推进癌症研究的新科学思想的研究工作的早期和概念阶段。

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.