Molecular mechanisms of pancreatic fibrogenesis
Principal Investigator: Brent A Neuschwander-Tetri
Abstract: [unreadable] 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. [unreadable] [unreadable]
Funding Period: 2004-05-01 - 2008-04-30
more information: NIH RePORT
- Induced thrombospondin expression in the mouse pancreas during pancreatic injuryBrent A Neuschwander-Tetri
Saint Louis University Liver Center and Department of Internal Medicine, Division of Gastroenterology and Hepatology, Saint Louis University School of Medicine, St Louis, MO, USA
Int J Biochem Cell Biol 38:102-9. 2006..These modulators of fibrogenesis could play a role in the development of pancreatic fibrosis that characterizes chronic pancreatitis...
- Protective role of angiotensin II type 2 receptor signaling in a mouse model of pancreatic fibrosisBarbara Ulmasov
Department of Internal Medicine, Saint Louis University School of Medicine, St Louis, MO 63110, USA
Am J Physiol Gastrointest Liver Physiol 296:G284-94. 2009..We propose that the effects of AII on injury-induced pancreatic fibrosis may be determined by the balance between AT1 and AT2 receptor signaling...