Critical to breaking through to a cure is the exploration of multiple facets of the scleroderma disease pathology in a strategic, focused approach. As cornerstones of the SRF program, collaboration and cross-institutional cooperation among scientists in a variety of disciplines broaden possibilities for innovation and discovery.

Research projects are evaluated annually at the SRF Scientific Workshop, where intensive review and discussion of the next critical steps take place. The workshop is a forum for leading scientists, from inside and outside the SRF program to provide new perspectives on the search for a cure, while promoting synergy among investigators and advancing the growing understanding of scleroderma.  

In Vitro Models of Vascular Dysfunction in Scleroderma
Nicholas Flavahan, Ph.D.
Heart and Lung Institute
The Ohio State University

Dr. Flavahan is building on his investigations into the processes of Raynaud’s phenomenon. With previous support from the SRF, Dr. Flavahan demonstrated that small blood vessels isolated from scleroderma skin have a defect in the activity of proteins called alpha2-adrenergic receptors. He has since shown that biological stress to blood vessels dramatically increases the number of these cold-sensitive receptors and could therefore greatly increase the blood vessels' sensitivity to cold.

Dr. Flavahan’s team is now studying the process underlying temperature sensitivity of these receptors, the rho kinase signaling pathway. Rho kinase is a protein that is activated by cold and in turn allows the receptors to function at cold temperatures. He hypothesizes that rho kinase inhibitors will have dramatic benefits in treating the vascular and other system abnormalities of scleroderma.

A second important dimension of Dr. Flavahan’s  work is to discover why scleroderma endothelial cells (cells lining the entire vascular system) do not respond correctly to blood flow. The defect may trigger closure of blood vessels and perhaps increased activity of the cold receptors, which could induce further reductions in blood flow.

Angiogenic Defects in Scleroderma
Michael Simons, M.D.
Dartmouth Medical School

Dr. Michael Simons has found evidence of possible angiogenic defects in scleroderma patients, which could help explain why scleroderma blood vessels do not repair themselves when damaged, as would occur in normal vessels. Angiogenesis is the complex process of formation and differentiation of blood vessels. Dr. Simons is pursuing initial findings that show distinctly different profiles in scleroderma patients with regard to levels of circulating angiogenic growth factors and inhibitors. Developing comprehensive profiles of scleroderma patient with regard to these levels could provide important diagnostic and prognostic information.

In addition, Dr. Simons’ studies focus on the role of HGF, an angiogenic growth factor, which was found to have decreased levels in scleroderma patient plasma. HGF is of particular interest not only as an angiogenic agent, but also as a strong inhibitor of fibrosis.

Dissecting the Contribution of Bone Marrow Stem Cells to Vascular Lesions in Scleroderma
Pascal Goldschmidt, M.D.
Duke University Medical Center

Dr. Goldschmidt is testing the hypothesis that the loss of blood vessels in scleroderma patients results from the possible deterioration of progenitor cells required for making, or regenerating, vessels. Dr. Goldschmidt’s earlier work, funded by the SRF, has suggested that scleroderma skin is a favorable environment for new vessels to develop, if the patient has an adequate supply of precursor cells needed to mount an angiogenic response.

Recent studies by Dr. Goldschmidt into the potential of Taxol as a treatment to address fibrosis in scleroderma resulted in substantial reduction in the amount of collagen detected in the skin. These early findings provide the basis for further study of the potential use of Taxol for treating fibrosis in scleroderma patients.

Scleroderma Autoantibodies
Antony Rosen, M.D.
Johns Hopkins University

The fibrotic process in scleroderma is accompanied by a unique autoimmune response, which targets a highly specific group of intracellular molecules. Since the autoantibodies generated by patients have both diagnostic and prognostic significance, Dr. Rosen’s studies are utilizing these autoantibodies as probes of disease mechanisms. Dr. Rosen has observed that all autoantigens in scleroderma are susceptible to cleavage, or splitting, by granzyme B, a protease (a type of enzyme) used by immune system cells to kill infected or cancerous cells. His studies are focused on understanding why this limited set of antigens is selected in scleroderma. His lab is addressing whether the scleroderma immune response is directed specifically against the unique forms of scleroderma antigens present in diseased tissues. Dr. Rosen is particularly interested in defining the changes in expression and conformation of these antigens that occur as a function of the cell cycle and tissue repair, with a view to modifying antigen availability therapeutically.

A Gene Expression Map of Scleroderma
Michael Whitfield, Ph.D.
Dartmouth Medical School

Dr. Whitfield’s primary tool for studying the cellular processes in scleroderma is the DNA microarray, which can examine the expression of all genes in the genome in a single experiment. Using this method to study skin biopsies from patients with diffuse scleroderma, he has found diverse gene expression patterns that emphasize the systemic nature of the disease and indicate that many different cell types are involved, including B lymphocytes, endothelial cells, fibroblasts and smooth muscle cells.

Dr. Whitfield is confirming and expanding this study with a larger number of patients to generate a comprehensive data set of the gene expression patterns in skin biopsies from normal volunteers and patients with limited or diffuse scleroderma. His second goal is to ask how the patterns of gene expression change during disease progression by examining skin biopsies in a group of patients as their disease progresses. From these studies, he hopes to gain an understanding of the cell biological basis of the disease, define molecular markers and clarify disease heterogeneity on a molecular level.

Molecular Markers in Scleroderma Skin
M. Kari Connolly, M.D.
University of California San Francisco

The overall aim of Dr. Connolly’s project is to identify new molecular markers and targets in scleroderma skin that correlate with disease subsets, activity and progression. She is collaborating with Dr. Michael Whitfield and other scientists in providing scleroderma patient tissue samples for analysis using DNA microarrays. This is a comprehensive, translational study that involves using an extensive clinical database to follow multiple clinical parameters over time. Dr. Connolly and her collaborators hypothesize that the skin contains clinically relevant molecular information about scleroderma. Through microarray analyses and correlating clinical and molecular data, it may be possible to develop new molecular markers that could identify which patients are at risk to develop internal organ involvement.

Scleroderma Center of Excellence
Fredrick Wigley, M.D.
Johns Hopkins University

The Scleroderma Center, directed by Dr. Fredrick Wigley at Johns Hopkins University, has evolved into a specialized Scleroderma Center of Excellence with a three-fold mission: 1) providing and coordinating comprehensive medical care for scleroderma patients and in particular, developing organ-specialty patient care for the complications of scleroderma. 2) educating patients, their families and primary care physicians in the local community; and 3) serving as a major resource and coordinating center for both clinical and basic research. The large population of patients at the Scleroderma Center, presenting all aspects of the disease process, provides unique and new insights into the disease and enables opportunities for novel clinical and basic research projects.

With SRF support, the Scleroderma Center expands its program this year, establishing new clinical programs to improve its capacity to care for scleroderma patients; expanding educational activities for patients and for physicians; and expanding both clinical and basic research through networking with investigators at other institutions and new relationships in the broader biotechnology community.