Current Research Projects

        Systemic sclerosis, or Scleroderma, is a systemic autoimmune disease characterized by widespread fibroproliferative vascular damage and progressive tissue fibrosis leading to severe multi-organ dysfunction. The fibroproliferative process occurs essentially in all organs but is often particularly evident and aggressive in the skin, kidneys and lungs, causing severe skin tightening and induration, Scleroderma Renal Crisis or Pulmonary Fibrosis and Arterial Hypertension (PAH), respectively.  These serious clinical events combined represent the major cause of symptoms and mortality in Scleroderma patients.  The following are some of the research projects currently being pursued at the Scleroderma Center and the Jefferson Institute of Molecular Medicine.

1. Role of the novel protein “caveolin-1” in the pathogenesis of tissue fibrosis and organ damage in systemic sclerosis.
   Recent studies on idiopathic PAH and idiopathic pulmonary fibrosis have identified caveolins, a family of membrane proteins, as important participants in the pathogenesis of both diseases.  Caveolin-1 (cav-1), the most important member of this family, is involved in numerous important biological functions including the regulation of two pathways universally accepted to play a crucial role in the pathogenesis of systemic sclerosis, namely the transforming growth factor β (TGF-β) and endothelin (ET-1) pathways.   Thus, the hypothesis to be tested in these studies is that cav-1 reduction plays a critical role in the pathogenesis of systemic sclerosis and that restoration of cav-1 levels may be a novel approach for the treatment of the fibroproliferative vascular damage and the tissue fibrosis of systemic sclerosis.
   
   
2. Vascular and biochemical alterations in scleroderma.
   Although the mechanisms involved in the development of Scleroderma are not completely known, it is clear that skin, visceral, and vascular fibrosis is responsible for the most severe clinical manifestations and the mortality of the disease. The overall objective of this study is to identify the important molecular events involved in the exaggerated production of collagen and in the vascular abnormalities in Scleroderma.  Several novel areas of investigation have been identified during our previous research studies, including the significant association of Scleroderma with the gene encoding Allograft Inflammatory Factor 1.  This is a protein which plays a crucial role in graft rejection, a process that resembles many features of Scleroderma.  Furthermore, we demonstrated that high levels of this protein are present in inflammatory and endothelial cells in Scleroderma-affected vasculature. Based on these results, we propose to test the hypothesis that this proteinplays an important role in the pathogenesis of the vascular abnormalities characteristic of Scleroderma.
   
   
3. Identification of biomarkers of Scleroderma disease severity and progression employing cDNA microarrays and proteomics.
   At the present time there are no available biomarkers that can provide information regarding the severity, progression, or response to therapy of Scleroderma.  Currently only clinical parameters, which are remarkably inaccurate and fraught with biases and variability, are employed.  This project will attempt to identify valuable biomarkers by employing global gene expression studies (microarrays), and proteomics followed by mass spectrometry analysis.
   
   

4. Assessment of severity of cutaneous fibrosis in Scleroderma and its response to treatment by confocal laser immunofluorescent microscopy.
   The extent and severity of skin fibrosis in Scleroderma are currently only assessed by cutaneous examination and palpation, a method which is non-quantitative, highly subjective, and usually not very reproducible.  There is a great need to develop an accurate and reliable method of quantifying the severity of fibrotic skin involvement.  These studies employ highly sophisticated methods of confocal immunomicroscopy to develop a quantitative method of assessment of the biochemical content and location of molecular component of the fibrous tissues.
   
   

5. Identification of novel intracellular cascades involved in the regulation of fibrosis.
   These studies employ state of the art molecular and genetic approaches to identify the complex intracellular pathways involved in the exaggerated production of fibrous tissue by scleroderma cells in order to identify new potential therapeutic targets.
   
   
6. Inhibition of exaggerated production of fibrotic tissue by Scleroderma fibroblasts involving novel therapeutic agents including rottlerin, CellCept, statins, biologics, and others.
   These studies are based on extensive prior experimental results from numerous research laboratories, including our own, and are aimed at testing potentially effective therapeutic agents in the laboratory by employing human skin cells in culture to identify the most promising candidate drugs with the potential to be developed into effective treatments for Scleroderma.
   
   
7. Creation of an animal model of Scleroderma by injection of cells from Scleroderma patients into mice lacking a functional immune system (Rag mice).
   At present there is no animal model which reproduces the clinical and pathologic features of Scleroderma.  Such an animal model would be an extremely valuable resource to study the mechanisms involved in the organ damage in Scleroderma and to test potential therapeutic agents.  We are employing a novel concept in attempts to develop a model for the disease by taking advantage of a genetic strain of mice which is unable to mount an effective immune response. In these studies we inject various types of cells obtained from the blood of Scleroderma patients into the immune deficient mice to identify which particular cells types are involved in the production of Scleroderma-like alterations and to test potentially effective therapeutic agents.
   
   
8. Treatment of pulmonary fibrosis in mice by an aerosol delivering cell permeable peptides capable of entering cells without a requirement for viral vectors.
   This study takes an innovative approach to treatment of one of the most serious and often lethal complications of Scleroderma by employing small molecules that are capable of being shuttled inside cells without using viral vectors.  These studies have the potential to develop an inhaler to deliver the effective drugs directly into the lung cells for the treatment of pulmonary fibrosis.