Idiopathic pulmonary fibrosis (IPF) is a nearly uniformly fatal disease marked by a progressive decline in lung Function and a median survival of 36 months. Fibroblastic foci are the pathologic hallmark of IPF and contain fibroblasts, myofibroblasts, and excess extracellular matrix (ECM), including fibrillar collagen. Through expression of procollagens, alpha-smooth muscle actin, and pro-fibrotic cytokines, myofibroblasts increase deposition and remodeling of the ECM and exhibit increased contractility, accounting for the abnormal structure and function of fibrotic lung. However, the lack of an affective treatment for IPF highlights our poor understanding of the key mediators that cause progressive fibrosis. Our laboratory has identified aortic carboxypeptidase-like protein (ACLP), a collagen-associated protein secreted by fibroblasts and myofibroblasts. The following observations from our previous work suggest an important role for ACLP in pulmonary fibrosis: 1) ACLP is highly expressed only in collagen-rich tissues 2) ACLP expression markedly increases in injured tissue, including the dermis and vasculature and 3) ACLP null mice have significantly impaired wound healing, a process that shares many features with pulmonary fibrosis. Our hypothesis is that ACLP is necessary for the development of pulmonary fibrosis.
In Aim 1 of this proposal we will examine ACLP expression in normal and fibrotic lung tissue and determine whether experimentally-induced lung fibrosis is altered in ACLP null mice.
Aim 2 will focus on the mechanisms through which ACLP regulates lung fibroblast remodeling of the collagen matrix. And, in Aim 3 we will determine whether ACLP over-expression increases experimentally-induced lung fibrosis. In addition to our scientific goals, this proposal includes the following goals for development of the principal investigator's career: 1) gain fundamental training in myofibroblast/smooth muscle cell biology, extracellular matrix biology, and modern molecular techniques 2) acquire the skills and experience needed to lead a research laboratory 3) serve as a tool for the principal investigator's transition from trainee to independent researcher in the field of pulmonary fibrosis. SUMMARY: Pulmonary fibrosis is a fatal disease caused by severe scarring of the lung with no known cause or cure. The goal of this proposal is to study a protein that may be necessary for forming scar in the lung with the hope of better understanding the disease so that new treatments can be found.
| Schissel, Scott L; Dunsmore, Sarah E; Liu, Xiaoli et al. (2009) Aortic carboxypeptidase-like protein is expressed in fibrotic human lung and its absence protects against bleomycin-induced lung fibrosis. Am J Pathol 174:818-28 |
