Over $1 Million Awarded in Research Grants

We are proud to announce that the Scleroderma Foundation has awarded $1,050,000 in research grants for 2008. The Foundation’s Peer Review Committee received and reviewed 35 grant applications from around the United States and after careful review and scoring —following the standards established by the National Institutes of Health—seven grants have been awarded to the top scoring applicants.

Two of the 2008 recipients are new investigators and fi ve are established researchers. The two top scoring grants received the Marta Marx and Mark Flapan awards. The Marta Marx Eradication of Scleroderma Award is funded by bequests from Marta Marx, who had scleroderma, and her brother Rudolph Juhl. The Mark Flapan Award is named for the late psychologist and scleroderma patient whose contributions to the Foundation’s publications and literature paved the way for greater patient understanding of the disease.

This year’s Marta Marx awardee is Patrizia Fuschiotti from the University of Pittsburgh. The Mark Flapan award goes to Mehrdad Abedi of Roger Williams Hospital, in Providence, Rhode Island.

The Scleroderma Foundation and its predecessor organizations have funded a total of 180 grants totaling more than $13.7 million since 1989.

The Foundation’s research program is indebted to the many researchers, M.D.s, Ph.D.s, and scientists who have donated their time and expertise over the past 20 years by serving on the Peer Review Committee. Special thanks go out to Dr. Richard M. Silver of Medical University of South Carolina who has served as Chair of the committee
for past two years. The commitment and dedication of the people who serve on the Peer Review committee is only matched by their pledge to scleroderma research and treatment.

And, of course, a tremendous debt of gratitude is owed to the many supporters of the Scleroderma Foundation and its chapters and support groups throughout the country. Thanks to the generous support of our donors, the Scleroderma Foundation remains the leading nonprofit organization funding peer-reviewed medical research to find the cause of and cure for scleroderma!

2008 Research Grant Recipients

Marta Marx Eradication of Scleroderma Award Recipient:
Patrizia Fuschiotti, Ph.D.
University of Pittsburgh, Pittsburgh, Pa.
"Genetic Control of Cytokine Production by Human CD-8+ and CD4+ T cells in Systemic Sclerosis (SSc)"

Scleroderma is a chronic disease characterized by the formation of scar tissue (fibrosis) in the skin, internal organs, and blood vessel walls. Although the disease’s underlying cause is not known, the body’s immune system appears to play a role by inducing inflammation and accumulation of T-cells (white blood cells) in the skin and other organs. T-cells are thought to secrete cytokines involved in the fibrotic damage. Cytokines are proteins with essential functions both in promoting and suppressing the action of immune cells. Studies indicate that alteration of this balance may be critical for the outcome of scleroderma. However, no specific correlation between cytokines and organ involvement has been found. In preliminary experiments, we found that peripheral blood T-cells from scleroderma patients make high levels of IL-13, a known pro-fibrotic cytokine, compared to healthy people, indicating dysregulation of cytokine production by T-cells. We hypothesize that scleroderma patients have a defect in the quantity of pro-fibrotic cytokines made by their T-cells. The goal of our research is the identification of an intrinsic/genetic defect in the production of an important pro-fibrotic cytokine that would provide a new mechanism for developing scleroderma by a majority of patients at risk for the disease and further open up avenues for therapeutic intervention.

Mark Flapan Award:
Mehrdad Abedi, M.D.
Roger Williams Hospital, Providence, R.I.
"Hematopoietic Origin of Fibroblasts at Sites of Injury"

Tissue fibroblasts are responsible for the development of connective tissue. Uncontrolled division of fibroblasts results in tissue fibrosis and scarring, a hallmark of many human diseases including scleroderma. Comprehending the nature of fibroblasts will increase our knowledge of fi brosis, ultimately leading to better treatment strategies both for wound healing and also the disease process. In injured tissue, fibroblasts are always thought to develop from the local connective tissue. Recently, however, a number of transplantation studies have revived the concept of bone marrow being a major source of tissue fibroblasts. Mesenchymal cells (supporting cells in the marrow that can give rise to connective tissue and blood vessels) have been expected to be the source of these marrow-derived fibroblasts. Nonetheless, recent experiments in our laboratory have found that mainly blood forming cells from the marrow are capable of producing fibroblasts in the injured skin. These findings provide us with the opportunity to determine novel markers/determinants in the development of the dermal fibroblast population. In this proposal, we will use the well-defined model of bone marrow differentiation to identify the intermediary cells between marrow stem cells and tissue fibroblasts. We will further study the nature of marrow derived fibroblasts in comparison to their endogenous counterparts to show that they are both fully functional and metabolically active. We believe that by identifying the elusive fibroblast progenitors and stem cells, we may be able to alter the nature of diseases such as scleroderma, in which fibroblasts play a critical role in pathology.

Sandeep Krishna Agarwal, M.D., Ph. D.
University of Texas Health Science Center, Houston, Texas
"Role of Cadherin-11 in Dermal Fibrosis"

The specific processes involved in scleroderma are unknown, but likely revolve around three components: an inappropriate immune response against the body, changes in the blood vessels, and over-activation of fibroblasts. Under normal conditions, fibroblasts are relatively quiet and largely responsible for providing the scaffolding of skin and our organs. However, in several autoimmune diseases, including scleroderma, these cells become activated, increase in number and release a large amount of mediators resulting in damage to skin and internal organs. The factors that determine these responses need to be better clarified. In this study, we will investigate how cadherin-11, a molecule found on fibroblasts, may contribute to these processes.

Cadherin-11 belongs to a larger family of molecules, called cadherins, that allow cells to adhere to each other. Cadherins have other functions beyond cell-tocell adhesion. Recent data emphasizes the importance of cadherin-11 in diseases that involve autoimmunity and fibroblasts, and since scleroderma is thought to involve both, determining if cadherin-11 is involved became of interest.

Therefore, we hypothesize that cadherin-11 expression is increased in scleroderma and localizes to a subtype of fibroblast cells, called myofi broblasts, where cadherin-11 influences the production of mediators involved in skin fibrosis. Further, we hypothesize that targeting cadherin-11 will be effective in decreasing dermal fibrosis in a mouse model of scleroderma.

Stephen Clark, Ph.D.
University of Connecticut Health Center, Farmington, Conn.
"Impact of the Ablation of TGF-B Signaling and SPARC Protein on the Fibrotic Phenotype in the TSK-2 Mutant Mouse"

A hallmark feature of scleroderma is an overproduction of molecules on the exterior of the cell. These exterior cellular molecules are required for normal cellular activity, however, when produced in excess, a condition termed fibrosis results. In scleroderma patients, this fibrosis is noticed as stiffening of the skin, however internal organs are also impacted, leading ultimately to organ failure. Mouse models are important tools for understanding the pathogenesis of human diseases. In the case of scleroderma, a mouse mutation called tight skin 2 (Tsk2) displays a cutaneous alteration similar to the dermal fibrosis observed in humans with scleroderma. In our study, we will employ the Tsk2 mutation in an effort to define the molecular pathways that are not functioning properly in the mutant mice, leading to the development of the dermal fibrosis seen in these mutant animals. Two additional strains of mice carrying alterations in genes that are important in the control of fibrosis will be used. These strains will be combined with the Tsk2 mutation with the goal of determining the interaction of molecules involved in the fibrotic process. Understanding the interplay of these molecules and their role in fibrosis is essential for the development of novel therapeutic interventions.

Francesco Del Galdo, M.D., Ph.D.
Assistant Professor, Jefferson Institute of Molecular Medicine; Associate Director, Scleroderma Center, Philadelphia, Pa.
"Inhibition of TGF-β PATHWAY BY CAVEOLIN-1, A Novel Treatment for Systemic Sclerosis?"

It is widely accepted that the excessive production of the potent profibrotic growth factor TGF-b  is a key step in the development of tissue fibrosis (scarring) occurring in Scleroderma. It was recently demonstrated that a small protein present in the surface of all cells, caveolin-1, plays a crucial role in regulating the activity of this growth factor. We recently found that both skin and lung tissues from Scleroderma patients contain less caveolin-1 than tissues from healthy individuals. Furthermore, we observed that mice genetically engineered to completely lack this protein show skin and lung fibrosis and develop pulmonary hypertension, abnormalities similar to those present in scleroderma. Thus, it appears that caveolin-1 plays a critical role in the pathogenesis of Scleroderma as an important regulator of the TGF-b pathway and ultimately of tissue fibrosis. In this research project we will investigate on the causes of the decrease of caveolin-1 in Scleroderma and we will test the therapeutic effects of caveolin-1 peptides on a mouse model that reproduces the fibrotic abnormalities of human Scleroderma. We believe that these studies will allow the identification of a novel therapeutic approach to prevent tissue fibrosis in Scleroderma.

Daniel J. Tschumperlin, BSME, MSE, Ph.D.
Harvard School of Public Health, Boston, Mass.
"Regulation of Dermal Fibroblast Biology by Substrate Stiffness"

Progressive fibrosis is a hallmark of systemic sclerosis (SSc) that results in stiffening of the skin and various internal organs, accounting for much of the morbidity and mortality associated with severe SSc. Preliminary data shows that increases in stiffness support increased fibroblast proliferation and attenuated apoptosis, the body’s method of getting rid of unneeded or abnormal cells, similar to that observed in SSc. This leads to a potentially powerful new paradigm for understanding progressive fibrosis, in which the mechanical environment in stiff tissue biases fibroblast behavior toward excessive proliferation. We propose two specific aims: to test the hypothesis that increases in substrate stiffness influences fibroblast behavior toward an activated, fibrosis-promoting state, and to test the hypothesis that fibroblast stiffness responses depend on tension generated within the fibroblast and adhesion to the substrate through particular cell surface receptors.

Using a newly developed approach that allows high throughput analysis of stiffness-dependent biology, we will characterize key aspects of fibroblast biology in cells grown on elastic substrates spanning the stiffness of normal and fibrotic dermal tissue. These experiments will establish whether local changes in stiffness are not just a downstream consequence of fibrotic disease, but also actively promote fibrotic progression through stiffness-dependent positive feedback effects. Insights gained here could stimulate novel therapeutic approaches aimed at halting or reversing fibrosis by targeting the interactions between fibroblasts and their mechanical environment.

Heather N. Yeowell, Ph.D.
Duke University, Durham, N.C.
"Regulation of Collagen Lysine Hydroxylation in Scleroderma Fibroblasts; Linkage of Alternatively- Spliced Forms of Lysyl Hydroxylase 2 to Fibrosis"

Collagens are a major component of skin. The level of collagen is increased dramatically in scleroderma. Collagen molecules are joined together by crosslinks that are responsible for its strength. However, a build-up of cross-links can cause the irreversible over-accumulation of collagen that contributes to scleroderma. Lysyl hydroxylase2 (LH2) is one of the enzymes responsible for collagen cross-link formation. Increased levels of cross-links in scleroderma have been correlated with the alternatively-spliced long form of LH2. Firstly, this proposal will examine whether levels of the long form of this enzyme vary between different forms of scleroderma, including systemic sclerosis and morphea. This may suggest different types of treatment. Secondly, as LH2 long is increased in scleroderma, this proposal seeks to find ways of decreasing it, thereby offering an opportunity for therapy. A group of proteins have been identified that have the potential to regulate levels of this LH2 long. These proteins will be introduced into scleroderma cells and the levels of the long form of LH2 will be measured by a very sensitive technique known as Polymerase Chain Reaction. If any of these proteins are shown to decrease the levels of LH2 long, this may suggest a potential therapeutic approach for scleroderma.