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Eileen Hsu, M.D. |
The Marta Marx Fund for the Eradication of Scleroderma
Eileen Hsu, M.D., University of Pittsburgh
Title of Project: IGF-II-mediated Fibrosis in Systemic Sclerosis
Lung complications are the leading cause of mortality in systemic sclerosis (SSc). Pulmonary fibrosis in SSc is the excessive accumulation of scar tissue in the lung. Few therapies exist that adequately treat this fatal complication. Pulmonary fibrosis is believed to be mediated by the interaction of several growth factors that stimulate scar formation in the lungs. We have previously reported that insulin-like growth factor-II (IGF-II) is increased in the lung tissues of patients with SSc-related pulmonary fibrosis. Furthermore, we have shown that IGF-II induces production of proteins that contribute to scar formation. By utilizing a unique bank of lung tissues from SSc patients who underwent lung transplantation at the University of Pittsburgh, we propose to study the mechanisms by which IGF-II induces lung fibrosis. We also propose to study the genetic mechanisms that regulate IGF-II overexpression in SSc lungs. We will also measure IGF-II in the blood stream of patients with SSc to determine if IGF-II is associated with other patient characteristics and if IGF-II is predictive of the development of pulmonary fibrosis. Our research studies will provide a novel mechanism of disease pathogenesis and may lead to new targets for drug therapy for SSc-related pulmonary fibrosis.
The Mark Flapan Award
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Harrison Farber, M.D. |
Harrison Farber, M.D., Boston University
Title of Project: The “PAH Phenotype” in Limited Systemic Sclerosis
Increased pressure in the blood vessels of the lungs (pulmonary hypertension; PH) is a common complication of scleroderma (SSc) and an important cause of mortality. Whether PH in scleroderma is similar to other forms of pH is not known. However, scleroderma is associated with damage to cells lining blood vessels (endothelial cells; EC) and increases in inflammation. In this grant, we will study whether changes in blood vessels increasing the risk of PH in scleroderma patients are due to EC damage and/or inflammation. We will study genes and proteins that could account for these changes in blood vessels and determine if they differ from genes and proteins in scleroderma patients who develop interstitial lung disease (lLD; scarring in the lungs). In sum, we are trying to find specific markers that determine which scleroderma patients develop PH, which scleroderma patients develop lLD, and which scleroderma patients develop neither PH nor lLD. Hopefully, these studies will find markers that could allow better screening and care of scleroderma patients and will determine better ways to monitor clinical course.
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Andreea Bujor, M.D., M.S. |
The Walter A. Coyle Memorial Research Grant Award
Andreea Bujor, M.D., M.S., Boston University
Title of Project: The Role of Caveolin-1 Overexpression in Scleroderma Fibrosis
Scleroderma (SSc) is a chronic progressive multiorgan disease. Among other symptoms, patients with this disease have excessive hardening of the skin (fibrosis) due to increased deposition of collagen by the cells in the skin called dermal fibroblasts. The pathogenesis of scleroderma is still poorly understood and there is no cure for SSc fibrosis. Several proteins in the fibroblasts of SSc patients are deregulated and it is believed that these alterations contribute to SSc skin fibrosis. In our proposal we hypothesize that overexpression of a protein called caveolin-1 has an important role in activating two pro-fibrotic signaling pathways in the fibroblasts of SSc patients: the Smad1 and PKCδ/Fli1 pathways. We propose to utilize recently developed technologies based on adenovirus overexpression and RNAi to investigate the effects of caveolin-1 deregulation in cultured SSc fibroblasts. In this study we will also use mouse models that overexpress caveolin-1 in their skin to understand the consequences of caveolin-1 overexpression in SSc patients. Our long term goal is to elucidate the role of aberrant caveolin-1 expression in SSc fibrosis, which may help select patients for future caveolin-1 based therapies.
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Jessica Gordon, M.D. |
Jessica Karen Gordon, M.D., Hospital for Special Surgery
Title of Project: Gene Expression Profiling and Predictors of Outcome in Systemic Sclerosis
The underlying cause of scleroderma is not completely understood, and, because of this, treatments for scleroderma are not curative. In this project we seek to improve our understanding of factors involved in the development of scleroderma, aspects which determine prognosis, and targets for therapy. Ongoing at our institution is a clinical trial evaluating the safety and efficacy of imatinib mesylate (Gleevec) for the treatment of diffuse scleroderma. Preliminary results show significant improvement in skin and lung parameters. In this project, we will use DNA microarray, a powerful tool
which enables us to measure the amount of production of over 38,500 genes from a single specimen on one gene-chip, to perform gene expression profiling on skin and blood samples from patients before and after treatment with imatinib and from controls. We will look for changes in gene expression with therapy and for predictors of response to imatinib. We will examine whether targets expressed in blood correlate with those seen in skin. Using these results we will validate potential biomarkers of disease activity and prognosis in a separate group of patients and controls. The knowledge gained in these investigations should provide new directions for the understanding of scleroderma.
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Erica Herzog, M.D., Ph.D. |
Erica Herzog, M.D., Ph.D., Yale University
Title of Project: Semaphorin 7a-Mediated Regulation of Fibrocyte Biology in Scleroderma ILD
Systemic Sclerosis (SSc) is a devastating disease in which the skin and internal organs are replaced by scar tissue and collagen. While great progress has been made in treating the kidney complications of this dreaded disease, lung complications have emerged as a major cause of mortality. One major category of scleroderma induced pulmonary involvement is Interstitial Lung Disease (ILD), or replacement of the gas exchange region of the lung with scar tissue. As there are only limited treatment options for this problem, many patients with SSc-ILD progress to respiratory failure and, ultimately, an untimely death. Thus, a greater understanding of the factors promoting lung fibrosis remains a great priority in this disease.
One emerging area of interest in this area is the role that certain types of immune cells called “fibrocytes” may play in the development of Scleroderma Lung Disease. Elegant studies by a number of investigators including our own have found that these cells, rather than being programmed to fight infection, are skewed towards a program of scar formation. Fibrocytes are associated with the development of scleroderma.
Unfortunately, the mechanisms that regulate fibrocyte biology are not well understood.
We have recently found a novel role for Semaphorin 7a in the differentiation and accumulation of fibrocytes in the diseased lung in a mouse model of pulmonary fibrosis and increased levels of Semaphorin 7a in the blood of patients with scleroderma-induced lung disease. This protein plays a pivotal role in brain development and has more recently been described as a regulator of immune cell activation. Aside from our preliminary work, there is no link between Semaphorin 7a, fibrocytes, and scleroderma. It is this area that our proposal seeks to explore.
Thus, Aim 1 of this proposal will determine the mechanism through which Semaphorin 7a affects the differentiation and activation of fibrocytes obtained from patients with scleroderma lung disease. Aim 2 will determine the mechanism and cell types through which Semaphorin 7a and its receptors promote or inhibit the differentiation and activation of fibrocytes in a mouse model of pulmonary fibrosis.
It is our belief that these highly innovative and robust studies will strengthen the novel association we have uncovered between Semaphorin 7a, fibrocytes, and SSc-ILD and perhaps provide insight into disease pathogenesis that could be used for the development of novel therapeutic targets for this otherwise incurable disease.
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Edward Leof, Ph.D. |
Edward Leof, Ph.D., Mayo Clinic Rochester
Title of Project: TGF-beta Regulated Fibrosis
Transforming growth factor ß (TGF-ß) is a multifunctional protein which can be either helpful or harmful to human health. While its ability to stimulate cell growth is important for normal wound healing, when unchecked the function of many organs can be disrupted by scar (i.e., fibrosis) formation. Since approximately 45% of mortality in the developed world is caused by some type of chronic fibroproliferative pathology, addressing this issue is critical. To that end, as the number of effective therapies are limited, the current application will, first test whether simultaneously targeting multiple TGF-ß pathways can provide the necessary preclinical data to generate a new Phase I/II clinical trial; and second, develop a novel bioassay to screen for small molecule inhibitors of fibrotic diseases, including scleroderma/systemic sclerosis.
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Arnold Postlethwaite, M.D. |
Arnold Postlethwaite, M.D., The University of Tennessee Health Science Center
Title of Project: SSc Platelet Phenotype Effected by Cytokines
It is generally believed that one of the initial events in hemostasis is the interaction of platelets with underlying collagen of the damaged vessel walls. When blood platelets come into contact with the damaged vessel wall, they clump together to form thrombi (clots). The vessel wall component involved in this process is thought to be a protein constituent known as collagen. Ongoing micro vascular injury is a hallmark of systemic sclerosis (SSc or scleroderma). The micro vascular injury is associated with micro thrombi (small clot) formation secondary to platelet aggregation.
Platelets are tiny fragments of cells called megakaryocytes. Under normal conditions, these platelets circulate in the blood vessel. When they come into contact with damaged vessel walls they become sticky. This property is caused by the chemical changes that occur inside of the platelets, which can trigger the stickiness of platelets. Under this condition, tanned platelets interact with each other to form small aggregates (micro thrombi). They affect blood circulation.
We hope to understand why chemical changes occur in platelets and what are the mechanisms that control the chemical changes, which could be used to modulate the activation of platelets that causes pathological thrombi formation in SSc. |
