Fibroblast Positional Identity in Scleroderma Pathogenesis
Howard Y. Chang, MD, PhD
Stanford University

Project Summary: Scleroderma (systemic sclerosis; SSc) is a disease characterized by excess fibrosis (hardening) in skin and other organs, but this fibrosis often occurs in a sitespecific fashion, providing a major clue to the pathogenesis of this disease. Dr. Chang believes that site-specific differences in fibroblasts may explain, in part; the predilection of SSc to occur in certain sites, and alterations in fibroblasts populations may cause excess fibrosis in SSc. Research has shown that fibroblasts, the cells responsible for fibrosis, isolated from different anatomic sites, are distinguishable from each other by the pattern of genes that are activated within them. Dr. Chang will perform experiments to characterize fibroblast populations from different anatomic locations in the skin of SSc patients to test his hypothesis.

What this project means for people with scleroderma: In scleroderma patients, the hardening of skin occurs in some places more than others. Understanding what gives skin from different anatomic sites their sensitivity or resistance to scleroderma could lead to new treatment strategies for scleroderma.

 

Systemic Sclerosis Associated Pulmonary Arterial Hypertension: Exploration in Transgenic Mice
Christopher P. Denton, MD, PhD, FRCP
Royal Free Hospital London and University College

Project Summary: Pulmonary arterial hypertension (PAH) is an important complication of scleroderma (SSc) and has a very high mortality.  Overall PAH is the single biggest cause of SSc-related death.  Its occurrence in only a subset of SSc cases suggests that multiple factors are likely to be involved.  Dr. Denton and his colleagues believe that SSc may involve a generalized defect in transforming growth factor beta (TGF-beta) bioactivity in fibroblastic cells and that in that background, PAH is more severe and may be more easily triggered.  In order to explore this hypothesis, they will start with their novel mouse model of SSc in which the activity of TGF-beta is disrupted in fibroblasts.  As in human SSc, approximately 25% of these mice develop symptoms of SSc, such as skin thickening and lung fibrosis.  Injury to lung epithelium induces fibrosis in 100% of this mouse strain.  These mice also develop structural changes in the pulmonary blood vessels, which leads Dr. Denton to believe they may have an associated susceptibility to pulmonary hypertension. Dr. Denton’s laboratory will investigate the development of pulmonary hypertension in this novel mouse model by asking whether stimuli such as hypoxia cause a more severe defect in this mouse strain than in controls.  If this is the case, then these mice may serve as a useful new model for SSc-associated pulmonary hypertension.  Such novel models for SSc-PAH are likely to provide a valuable platform for investigating therapeutic effects and exploring the potential synergy between different PAH therapies in vivo.

What this project means for people with scleroderma: There are unique features of pulmonary hypertension in scleroderma.  This project will lead to better recognition of the key abnormalities that determine the development of PAH in scleroderma and help improve the use of new therapies as they become available.

 

The Function of T-bet, Innate Immunity and Type-2 Cytokines in Scleroderma
Laurie Glimcher, MD
Harvard University

Project Summary: Scleroderma is an autoimmune disorder characterized by excessive fibrosis of the skin and internal organs. Certain growth factors, cytokines, are secreted by cells of the immune system and promote inflammation as well as fibrosis. A shift in the T cell cytokine profile towards “profibrotic” cytokines (referred to as Type 2), such as Interleukin-4, Interleukin-13 and Transforming Growth Factor-beta (TGF beta), and away from the protective Type 1 cytokine, Interferon-alpha, has been documented in patients with scleroderma and in mouse models of this disease. Transcription factors shape immune responses by regulating the expression of cytokines. For example, T-bet activates and represses Type 1 and Type 2 cytokines, respectively. Dr. Glimcher and her colleagues have recently found that mice deficient in the transcription factor T-bet, develop more severe bleomycin-induced skin fibrosis, a model of the distinctive skin changes of scleroderma. Interestingly, the action of T-bet was mapped to cells in the innate immune system, where T-bet represses Interleukin-13. Dr. Glimcher and her colleagues are translating these findings to a more relevant mouse model of human scleroderma, chronic graft versus host disease. They believe that scleroderma may be prevented or treated by blocking
Interleukin-13 or augmenting the activity of T-bet in the immune system.

What this project means for people with scleroderma: Blocking Interleukin-13 is predicted to ameliorate the pro-fibrotic response in the skin and internal organs of patients with scleroderma. Moreover, expression of T-bet in cells of the immune system by targeted gene therapy is a promising future treatment for this currently intractable disease. Moreover, expression of T-bet in cells of the immune system by targeted gene therapy is a promising future treatment for this currently intractable disease.

 

Cytokine, Chemokine and Chemokine Receptor Expression in Scleroderma Skin
Alisa Koch, MD
University of Michigan

Project Summary: Dr. Koch’s laboratory and others have shown cytokines that serve and “anti inflammatory role” in some diseases such as rheumatoid arthritis can be used to modulate the disease and their work aims to validate whether such an approach might be therapeutically appropriate in SSc. Thus, Dr. Koch and her colleagues are comparing levels of cytokine, chemokine and chemokine receptor expression in scleroderma skin biopsies to the levels found in normal skin biopsies. Some cytokines affect angiogenesis (the formation of new blood vessels); therefore, they are also examining the balance of pro-angiogenic and anti-angiogenic cytokines in the tissues. These studies will provide insight into which factors aid in the recruitment of inflammatory cells in scleroderma, how blood vessel dysregulation occurs in scleroderma and whether modulation of these factors may affect disease progression.

What this project means for people with scleroderma: An understanding of key cytokines, chemokines and chemokine receptors that are abnormally expressed in scleroderma may provide new targets for therapeutic intervention.

 

Cellular and Biochemical Modulation of Inflammation and Fibrosis in the Scleroderma Lung
Vibha Lama, MD, MS, and David Pinsky, MD
University of Michigan

Project Summary: Drs. Lama and Pinsky are examining the mechanisms of inflammation and fibrosis in the lungs of scleroderma patients. Using a novel animal model of graft rejection, they are evaluating the ability of lung-resident mesenchymal stem cells to influence inflammation and fibrosis. They will also investigate the roles of certain regulatory molecules which occur naturally in the body called eicosanoids (as well as their synthetic analogues) in modulating inflammation and fibrosis in the lung.

What this project means for people with scleroderma: Understanding how lung-resident mesenchymal stem cells and eicosanoids modulate fibrosis may lead to therapies to prevent or ameliorate lung disease in scleroderma.

 

Scleroderma and the Immune Mechanism Mediating Pulmonary Vascular Disease
Marlene Rabinovitch, MD                                                                                     
Stanford University

Project Summary:  A substantial subset of scleroderma patients develops severe pulmonary arterial hypertension (PAH).  Dr. Rabinovitch’s laboratory is developing a mouse model of scleroderma PAH that is inducible with an external stimulus.  They have developed a transgenic mouse which over-expresses S100A4/Mts1, a protein which is highly expressed in rheumatoid arthritis in man and which they believe may be important in scleroderma.  When aged, S100A4/Mts1 over-expressing mice are inoculated in the lungs with a virus that targets vascular cells (gamma HV-68); the mice develop occlusive pulmonary arterial lesions.  These lesions have certain pathologic features that resemble the lesions seen in patients with scleroderma.  Also, more severe pulmonary lesions develop in the S100A4/Mts1 versus the normal mice, suggesting a heightened susceptibility of the pulmonary arteries in the S100A4/Mts1 transgenic mouse.  Based on related, ongoing work in Dr. Rabinovitch’s laboratory, their current hypothesis is that elastase, a protein that is a critical regulator in the vascular wall, is being degraded, leading to this heightened susceptibility. 
  
What this project means for people with scleroderma:  This work suggests that environmental stimuli like certain viral infections might be triggers or susceptibility factors for the disease. Understanding scleroderma pathogenesis is critical to identifying ways to intervene and treat the disease. 

 

A Model System for T Cell Targeting of the Vascular Endothelium
Ann Marshak-Rothstein, PhD
Boston University

Project Summary:  Systemic sclerosis (SSc) can be a debilitating chronic inflammatory disorder associated with severe alterations of vascular tissue and excessive fibrosis of the skin and other internal organs.  A number of factors implicate an immunological imbalance in at least the initial stages of this disorder, but the target tissue and type of immune response that promotes the unique features of this disease remain poorly defined.  Dr. Marshak-Rothstein and her colleagues believe that the nature of immune response is determined by the local microenvironment in which an immune response takes place.  Since vascular dysfunction is one of the earliest manifestations of SSc and is commonly associated with infiltration of activated T cells around blood vessels, it is possible that the distinct pathology of SSc and the unique set of autoantigens targeted in SSc reflect initial damage to the vasculature mediated by an effector T cell population.  To test this premise, they intend to establish an experimental model that will allow them to specifically target effector T cell populations to the vascular endothelium.  They will then use this model to examine other fundamental aspects of the immune stimulus and response.

What this project means for people with scleroderma:  These studies should establish a highly reproducible mammalian model of SSc that should allow investigators to identify and modulate the immunological parameters that lead to chronic vascular diseases such as systemic sclerosis.

 

The Vascular Biology of Scleroderma
Stephen Schwartz MD, PhD
University of Washington (Seattle)

Project Summary:  Dr. Schwartz’s laboratory is working to understand to understand the vascular injury that occurs in scleroderma.  They have determined that capillaries (the smallest caliber blood vessels) disappear in scleroderma. This vasculopathy seems to be a very early step in the disease, perhaps leading to the connective tissue changes (fibrosis) or even to the events that initiate the autoimmune response.  Through various studies, including molecular studies looking for certain proteins in the cells of the blood vessels (histology), microarrays that quantify the expression levels of all the genes in certain cells, and analyses of proteins present in the blood,  Dr. Schwartz and his colleagues have identified specific vascular proteins having differential expression in scleroderma and normal vessels. In particular, Dr. Schwartz and his colleagues have focused on VE-cadherin. They believe that VE-cadherin, a molecule typically seen on the surface of endothelial cells and one that is required to assemble the lining of blood vessels, may be missing from the cells lining SSc blood vessels.  This may be a critical factor in the loss of capillaries seen in scleroderma.  They are also developing a cell culture assay to explore mechanisms of blood vessel loss in scleroderma.
What this project means for people with scleroderma:  It may be possible to specifically activate endothelial cells in SSc patients to re-express VE-cadherin.  Alternatively, it may be possible to block the process that leads to shutting off the VE-cadherin expression.  If effective, the now normalized endothelial cells would then support the regeneration of capillaries in patients. 

 

Anti-Angiogenic Factors in Scleroderma
Michael Simons, MD
Dartmouth Medical School

Project Summary:  Dr. Simons hypothesizes that scleroderma involves an initial tissue injury which leads to activation of certain enzymes in the extracellular matrix called matrix proteases. This activation results in the breakdown of other proteins in repair cells, generating protein fragments which elicit an autoimmune response.  Some of these protein fragments are anti-angiogenic; that is, they prevent blood vessel growth.  This may account for some of the complications of the disease including poor wound healing, tissue loss and pulmonary hypertension.  The goal of this project is to characterize the anti-angiogenic abnormalities in the blood of patients with scleroderma and establish a relationship of these abnormalities with disease activity and severity.

What this project means for people with scleroderma:  The Simons lab work suggests that scleroderma can be prevented or treated by blocking inappropriate matrix breakdown.  In addition, if the hypothesis is validated, it would suggest that the anti-angiogenic protein fragments that the matrix breakdown generates can be neutralized to ameliorate the disease.

 

The Johns Hopkins Scleroderma Center of Excellence
Fredrick M. Wigley, MD
Johns Hopkins University School of Medicine

Project Summary:  The goals of the Johns Hopkins Scleroderma Center are to sustain and enhance a specialized Scleroderma Center that provides and coordinates comprehensive medical care for patients with systemic sclerosis; to be a major resource and coordinating center for both clinical and basic science research; and to develop and administer educational programs for patients, professionals and trainees.  Over 200 new patients continue to be seen each year at the Center; patients with scleroderma, Raynaud’s phenomenon, localized scleroderma, mixed connective tissue disease or diseases that mimic scleroderma.  The Center now has over 2,000 scleroderma patients in its clinical database; Center physicians evaluate and manage 4-7 new scleroderma patients and over 50 return scleroderma patients each week.  The Center is involved in both clinical and basic research and has established a robust translational research program that uses patient information and materials for new discovery.  Currently, the Center has over 10 active clinical studies which include investigations into novel therapies for scleroderma.  The Center was a critical component of an inter-departmental group at Hopkins led by Paul Hassoun that was recently awarded a 5-year and $20 million grant by the National Institutes of Health. 

What this project means for people with scleroderma:  The Center plays an important role in the daily care of patients with scleroderma.  It is a leading center for clinical studies of new therapies.  Its basic and translational research will provide new insights into the pathogenesis of the disease which may lead to effective new therapies.

 

A Gene Expression Map of Scleroderma
Michael L. Whitfield, PhD
Dartmouth Medical School

Project Summary:  Scleroderma is a disease with a heterogeneous presentation including changes in internal organ systems, blood vessels, and skin.  Quantitatively characterizing the disease with current clinical measures has proven difficult, which has made comparison of patient populations and the tracking of disease progression challenging.  A new tool, the DNA microarray, measures the expression of every gene in the genome in a single experiment and provides a method to quantify, at a molecular level, the complex physical manifestations of scleroderma. Our goal is to use these measurements to identify “gene expression signatures” that correlate with patient subgroups such as type of disease, severity or particular complications, as has been done in other diseases such as breast cancer.  The ability to identify such patient subgroups will help to connect patients with the most appropriate course of treatment.  Additionally, we are working to identify “biomarkers” or particular measurements from the gene expression signatures that can be used to predict outcomes for the patients.

Our initial set of data from scleroderma samples shows evidence of multiple distinct subgroups that can be distinguished by their unique gene expression signatures.  Some of these subgroups reflect recognized clinical classifications, such as the distinction between limited and diffuse scleroderma, while others represent previously unrecognized groups.  

What this project means for people with scleroderma:  The identification of novel disease subtypes, their underlying molecular defect and diagnostic biomarkers will lead to a better understanding of pathogenesis and ultimately the ability to produce targeted therapies.  The result would be earlier diagnosis and potentially to treatments tailored to each subtype.

 

Non-Invasive Imaging of Scleroderma Vasculature in Scleroderma Patients
Chun Yuan, PhD
University of Washington (Seattle)

Project Summary:  The current approach to quantifying scleroderma disease largely depends on the skin score, which is relatively subjective and does not take into account vascular changes.  However, changes in the capillaries in the nail bed (nailfold) have been documented early in the progression of scleroderma and may be a highly accurate diagnostic and prognostic tool. 
The goal of this project is to develop comprehensive, high resolution, non-invasive magnetic resonance imaging (MRI) techniques to evaluate scleroderma.  Dr. Yuan and his colleagues have focused on developing a non-invasive, highly reproducible finger vascular imaging technique which will examine disease status in finger tissue, arterial and capillary vasculature and assess disease progression and regression.  They have developed several techniques for higher resolution finger imaging as well as a dedicated high-resolution finger coil with which they are now able to measure the size of the digital artery, the thickness of the vessel wall and the thickness of the dorsal skin of a scleroderma patient’s finger.  The high-resolution finger coil also makes it possible to observe tissue content alterations and vascular density changes caused by the disease. 

What this project means for people with scleroderma:  If these techniques can be refined, they can be used to quantitatively evaluate the morphological changes in the blood vessels of scleroderma fingers.  The prediction is that this measure would be a vast improvement on the current gold standard of “scoring” the disease, the Rodnan skin score.  This MRI technique might also be used to evaluate the progression/regression response after treatment and so enable better treatment of patients.

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