Molecular mechanisms of pancreatic fibrogenesis

描述(由申请人提供)：在过去的40年里，广泛的实验工作使人们在形态和生化水平上对急性和慢性胰腺炎有了更好的了解。然而，这些进展并没有带来有效的预防和治疗策略。这项工作的广泛目标是在分子水平上更好地了解慢性胰腺炎的病理生理学，以便指导未来的预防和治疗策略。这一目标将通过专注于导致胰腺纤维化的关键介质--胰腺星状细胞激活的关键细胞外事件来实现。这项建议的目的是对主要研究人员开展的前期工作的合理扩展，以发展一种概括慢性胰腺炎形态变化的小鼠模型，开发必要的工具来测量胰腺纤维化的有意义的终点，并寻找在重复损伤期间在胰腺中表达的新基因。明确血管紧张素II及其受体在胰星状细胞活化和慢性胰腺炎发生发展中的作用，以及血栓反应蛋白-1和凝血酶反应蛋白-2在反复损伤时激活胰星状细胞中的功能意义。第一个目标将通过使用血管紧张素原和血管紧张素II受体基因缺失的小鼠以及小鼠和培养的胰腺星状细胞中高度特异的受体拮抗剂来实现。第二个目标将通过使用凝血酶反应蛋白基因敲除的小鼠来实现，以确定凝血酶反应蛋白-1和凝血酶反应蛋白-2在胰腺星状细胞激活中的作用。实现这些目标将填补对慢性胰腺炎认识的重大空白，这一新的知识可能有助于确定有效的治疗方法。

DESCRIPTION (provided by applicant): Extensive experimental work over the past four decades has led to a better understanding of acute and chronic pancreatitis at the morphological and biochemical level. However, these advances have not led to effective preventive and therapeutic strategies. The broad goal of this work is to better understand the pathophysiology of chronic pancreatitis at the molecular level in order to guide future preventive and therapeutic strategies. This goal will be accomplished by focusing on key extracellular events that lead to activation of the pancreatic stellate cell, the key mediator of pancreatic fibrogenesis. The aims of this proposal represent logical extensions of the preliminary work undertaken by the principal investigator to develop a mouse model that recapitulates the morphological changes of chronic pancreatitis, develop the necessary tools to measure meaningful endpoints of pancreatic fibrogenesis, and seek novel genes expressed in the pancreas during repetitive injury. The specific aims are to establish the role of angiotensin II and its receptors in the activation of pancreatic stellate cells and development of chronic pancreatitis and to establish the functional significance of thrombospondin-1 and thrombospondin-2 in the activation of pancreatic stellate cells during repetitive injury. The first aim will be accomplished by using mice with genetic deletions of angiotensinogen and angiotensin II receptors as well as highly specific receptor antagonists in mice and cultured pancreatic stellate cells. The second aim will be accomplished by using thrombospondin knockout mice to establish the role of thrombospondin-1 and thrombospondin-2 in pancreatic stellate cell activation. Accomplishing these aims will fill significant gaps in the understanding of chronic pancreatitis and this new knowledge may help identify effective treatment approaches to this disease.