The broad, long-term objectives are to determine the role played by connective tissue growth factor (CTGF) in promoting pancreatic fibrosis, which is a common feature of chronic pancreatitis. CTGF stimulates vital biological processes such as chondrogenesis, angiogenesis and matrigenesis via its regulation of cell proliferation, migration, transdifferentiation and production of extracellular matrix molecules. CTGF knockout mice exhibit lethal angiogenic and skeletal defects, while subcutaneous injection of CTGF causes dermal fibrosis. CTGF is over-expressed in many fibrotic lesions and acts downstream of transforming growth factor- beta (TGF-beta) in driving fibrosis. During pancreatitis, CTGF is over-expressed by several cell types and acts via autocrine and paracrine pathways to regulate the function of pancreatic stellate cells (PSCs), the principal fibrogenic cell type in the pancreas. CTGF thus holds promise as a new therapeutic target in strategies designed to prevent or reverse pancreatic fibrosis. Our hypothesis is that CTGF production in PSC is stimulated by alcohol and that CTGF drives pro-fibrogenic and anti-apoptotic pathways in PSC through its binding and activation of integrin alpha5beta1 (a5b1), a novel CTGF receptor.
The Specific Aims to test this hypothesis are 1. To determine the effect of ethanol and its metabolites on the production of CTGF in PSC; these studies will assess the effect of ethanol, acetaldehyde or fatty acid ethyl esters on CTGF production, the involvement of oxidant stress and TGF-beta, and the role of CTGF in autocrine regulation of PSC function; and 2. To determine the responses of PSC to CTGF and the role of integrin a5b1; these studies will address the expression, regulation, and activation of integrin a5b1 in PSC, will assess the role of integrin a5b1 in mediating pro-fibrogenic and anti-apoptotic signaling in PSC by CTGF, and will assess the role of CTGF in promoting fibrogenesis in vivo when administered against a background of acute pancreatitis in mice. The relevance of these studies to public health is that they will identify the mechanisms by which CTGF regulates PSC function and pancreatic fibrosis, and will thus lead to new treatment modalities. ? ? ?
