Diverse injury to the lung from endogenous as well as environmental factors or agents may result in a stereotypic response leading to fibrosis and end stage lung disease with a potential fatal outcome. The long term objectives of this project are to determine the mechanisms underlying the genesis of the myofibroblast in lung injury and fibrosis, and to characterize the functional phenotype and roles of these cells in pulmonary fibrosis. The myofibroblast is a key source of mediators and extracellular matrix whose expression in fibrotic lesions is markedly stimulated. Fibrotic foci composed of myofibroblasts and other fibroblast phenotypes are diagnostic of idiopathic pulmonary fibrosis, a virtually fatal disease with no effective therapy. Hence understanding how these cells arise and the mechanisms regulating their survival may provide novel insight into the pathogenesis of pulmonary fibrosis. A number of mediators are known to induce myofibroblast differentiation in fibroblasts, however recent studies suggest additional derivation from epithelial cells through a process termed epithelial-mesenchymal transition (EMT). The central hypothesis of the proposal is that mediator induced genesis of the myofibroblast is dependent on regulation by transcription factors and their cognate elements in the alpha-smooth muscle actin ((-SMA) promoter, and that expression of (-SMA has consequences on elaboration of other key elements of the myofibroblast phenotype and concomitant loss of epithelial phenotype in EMT. To test this hypothesis, four specific aims are proposed. First, transcriptional regulation of myofibroblast differentiation will be analyzed from the standpoint of (-SMA gene expression. Second, epigenetic mechanisms involved in regulation of this differentiation will be investigated. Third, the functional role of (-SMA gene expression will be analyzed with respect to its effects on key signaling pathways, gene expression, and cell survival/apoptosis. The role of (-SMA in inducing the cellular phenotypic features of the myofibroblast will be identified by examining the effects of specific inhibitors of its expression and ectopic or induced expression in cells not usually known to express this actin isoform. Finally, the specific impact of induced (-SMA expression on EMT will be examined by analysis of the effects on cellular signaling and expression of epithelial marker genes. The proposed work should reveal novel insights to understanding processes associated with the multitude of diseases known to cause fibrosis. PROJECT NARRATIVE. The proposed studies attempt to uncover key biological processes that are important in the emergence of an activated fibroblast phenotype in fibrotic diseases of the lung, such as idiopathic pulmonary fibrosis and lung disease associated with autoimmune diseases such as rheumatoid arthritis. Thus the project is directly relevant to improving current understanding of these diseases, many of which such as idiopathic pulmonary fibrosis, have no current effective treatment and often result in chronic lung disease with a fatal outcome. Such fibrosis or scarring may also affect lung diseases with increasing prevalence, such as asthma. Improvement in understanding these processes will provide much needed insight into potentially novel treatments as well as approaches for management of patients with these diseases. ? ? ?
Showing the most recent 10 out of 63 publications
