Molecular mechanisms of pancreatic fibrogenesis

描述（由申请人提供）：在过去的四十年中，大量的实验工作已经在形态学和生化水平上更好地理解了急性和慢性胰腺炎。然而，这些进步并没有导致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，以指导未来的预防和治疗策略。这一目标将通过关注导致胰腺星状细胞激活的关键细胞外事件来实现，星状细胞是胰腺纤维形成的关键介质。该提案的目的是对首席研究员开展的初步工作的逻辑延伸，该研究旨在建立一个小鼠模型，概括慢性胰腺炎的形态学变化，开发必要的工具来测量胰腺纤维形成的有意义的终点，并在胰腺中寻找重复损伤期间表达的新基因。具体目的是确定血管紧张素II及其受体在胰腺星状细胞的激活和慢性胰腺炎的发展中的作用，并确定血栓spondin-1和血栓spondin-2在重复损伤中胰腺星状细胞激活中的功能意义。第一个目标将通过在小鼠和培养的胰腺星状细胞中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高度特异性受体拮抗剂来实现。第二个目标将通过使用血小板反应蛋白敲除小鼠来确定血小板反应蛋白-1和血小板反应蛋白-2在胰腺星状细胞活化中的作用。实现这些目标将填补对慢性胰腺炎认识的重大空白，这一新知识可能有助于确定这种疾病的有效治疗方法。

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.