Our long-term goal is to develop novel treatments for scleroderma lung disease and other diseases involving lung fibrosis. Currently, there are no effective therapies. Preliminary Studies have identified caveolin-1 as a signaling molecule that regulates collagen expression and therefore is an outstanding target for such therapies. Indeed, when lung disease is induced in mice using bleomycin, systemic treatment with a caveolin-1 agonist peptide causes a dramatic improvement by several criteria. While these positive effects may result directly from the inhibition of collagen expression, it is also quite possible that caveolin-1 is acting by inhibiting inflammation, given that the processes of tissue damage, inflammation, and overexpression of collagen are so intertwined in space and time that it is extremely difficult to determine whether one precedes the others or whether these insults to the lung continually exacerbate each other. Therefore, we will test the hypothesis that uprequlatinq caveolin-1 expression/activity in vivo will provide protection against lung fibrosis by directly inhibiting collagen expression and/or by inhibiting inflammation. Specifically we will: 1) Optimize the delivery of the caveolin-1 agonist peptide and full-length caveolin-1 encoded by viral vectors. Once we have optimized the delivery of caveolin-1 agonist peptide and full-length caveolin-1, we will: 2) Determine whether upregulating caveolin-1 expression/activity in vivo directly inhibits the differentiation of myofibrpblasts (the cells responsible for the over-expression of collagen in fibrotic lung diseases) and their expression of collagen, and 3) Determine whether up-regulating caveolin-1 expression/activity in macrophages and PMNs in vitro and in vivo alters immune functions. Successful completion of these studies will require that I become well-trained in the three targeted areas of this K01 application (use of animal models, viral delivery of genes in vivo, immunology) and will demonstrate that upregulating caveolin-1 expression/activity in vivo is likely to be an effective therapy for scleroderma lung disease. Lav language regarding relevance to public health - There are currently no effective treatments for lung diseases in which the tissue becomes stiff or fibrotic, making it very difficult for the patient to breathe. Using a mouse model of fibrotic lung disease, we have already shown that increasing the activity of a protein known as caveolin-1 provides substantial benefit. We will further explore caveolin-1 as a treatment for lung fibrosis by finding the optimal treatment conditions and by determining whether the treatment works by simply blocking the stiffening of the tissue, by blocking tissue damage caused by overactive cells from the immune system, or through both of these mechanisms.
| Reese, Charles; Perry, Beth; Heywood, Jonathan et al. (2014) Caveolin-1 deficiency may predispose African Americans to systemic sclerosis-related interstitial lung disease. Arthritis Rheumatol 66:1909-19 |
| Lee, Rebecca; Reese, Charles; Bonner, Michael et al. (2014) Bleomycin delivery by osmotic minipump: similarity to human scleroderma interstitial lung disease. Am J Physiol Lung Cell Mol Physiol 306:L736-48 |
| Reese, Charles; Dyer, Shanice; Perry, Beth et al. (2013) Differential regulation of cell functions by CSD peptide subdomains. Respir Res 14:90 |
| Tourkina, Elena; Hoffman, Stanley (2012) Caveolin-1 signaling in lung fibrosis. Open Rheumatol J 6:116-22 |
| Silver, Richard M; Bogatkevich, Galina; Tourkina, Elena et al. (2012) Racial differences between blacks and whites with systemic sclerosis. Curr Opin Rheumatol 24:642-8 |
| Bains, S N; Tourkina, E; Atkinson, C et al. (2012) Loss of caveolin-1 from bronchial epithelial cells and monocytes in human subjects with asthma. Allergy 67:1601-4 |
| Tourkina, Elena; Richard, Mathieu; Oates, James et al. (2010) Caveolin-1 regulates leucocyte behaviour in fibrotic lung disease. Ann Rheum Dis 69:1220-6 |
| Tourkina, Elena; Richard, Mathieu; Gooz, Pal et al. (2008) Antifibrotic properties of caveolin-1 scaffolding domain in vitro and in vivo. Am J Physiol Lung Cell Mol Physiol 294:L843-61 |
