Novel Pilot Projects
The Novel Pilot Projects Program supports novel, innovative pilot projects to forward lupus research by providing start-up funds to initiate new studies. These grants are critically important for continued progress in lupus research in the face of shrinking resources from the National Institutes of Health due to federal budget constraints. The Foundation supports novel studies that will accelerate research related to the causes, treatments, prevention and cure of lupus and research to test new approaches and develop experimental prototypes.
Novel Pilot Projects Funded in 2008
"Are microRNA, Novel Regulators in Immunity, Involved in Autoimmune Lupus?"
Ansar Ahmed, Ph.D., D.V.M.
Professor & Head, Biomedical Sciences and Pathobiology
Virginia Polytechnic Institute and State University
This grant award is presented in memory of Kassie McMullin Biglow
A major, exciting finding in gene regulation is the recent identification of small ribonucleic acids, called microRNA (miRNA). Already, their biomedical impact in tumorigenesis, development, and cell function has been reported. Further, the role of miRNA in homeostasis of the immune system has been reported, which proposes an entirely new paradigm of regulation of immunity. Our recent studies have shown that estrogen, a promoter of autoimmune lupus, regulates the expression of miRNA in spleen cells of normal (non autoimmune) C57BL/6 mice. To date, studies on dysregulated miRNA in autoimmune states are very limited. Therefore, the goal of the proposed studies is to investigate the role of miRNA in the pathogenesis of systemic lupus erythematosus (SLE) using autoimmune prone NZB/W mice, a well-tested, classical model of human lupus. Given the role of miRNA in immune regulation, the hypothesis that aberrant expression of miRNA may occur in autoimmune states such as in autoimmune lupus is plausible. We will identify signature miRNA expressed in spleen cells from NZB/W mice during active disease states. Further, we anticipate that manipulation of lupus related miRNA activity in spleen cells from mice with active disease will ameliorate production of autoantibodies, as well as inflammatory cytokines. Our studies may provide unique, novel, molecular diagnostic markers for lupus, and offer entirely new therapeutic approaches, such as manipulation of lupus-related miRNA, to correct pathological conditions.
"C4d on Circulating Cells and Renal Tissues as Markers of Lupus Nephritis"
Amy Kao, M.D., M.P.H.
Assistant Professor of Medicine
University of Pittsburgh
Lupus Center for Excellence, Pittsburgh, PA
This grant is provided by the Louis Berkowitz Family Foundation.
SLE is a systemic autoimmune disease characterized by variable clinical manifestations and disease courses. Accurate means for monitoring kidney disease severity and activity are in urgent need. We have recently developed a unique assay for measuring complement proteins on circulating cells of SLE patients. We will determine the use of this assay for severity and activity of kidney inflammation due to SLE. These studies will enhance our understanding of the mechanisms and lead to improved monitoring of activity and response to therapy of lupus kidney disease.
Video: Watch Dr. Kao speak about her research
"Generation of Regulatory T Cells in Lupus Using Mesenchymal Stem Cells"
Westley Reeves, M.D.
Professor & Division Chief, Rheumatology & Clinical Immunology
University of Florida, Gainesville
This grant award is provided by funds contributed through a trust created in memory of Stephen and Catherine Pida
Mesenchymal stem cells (MSC) are adult stem cells that can be isolated from the bone marrow or other tissues. They have the useful property of being immunosuppressive and potentially can be used to stimulate the production of regulatory T lymphocytes. We found that they increase the expression of a protein important for the development of these regulatory cells called Foxp3 and that increased Foxp3 expression is associated with the downregulation of autoantibodies in mice with lupus. Since MSC are easy to grow in culture and are readily amenable to gene therapy, we propose to exploit these unique properties to direct immunosuppressive (regulatory) T cells to affected tissues in lupus. Mice with lupus will be treated with MSC to see if we can turn off the production of lupus autoantibodies and reverse or prevent the development of inflammatory disease in the kidneys (lupus nephritis) and lungs (pulmonary vasculitis). If successful, the same approach could be translated readily into humans. In the future, MSC could be isolated from adult bone marrow, blood, or adipose tissue (fat), modified (if necessary) using gene therapy, and reinfused into patients as a treatment for the inflammatory manifestations of SLE.
"Mechanisms of Organ Damage in Males with Lupus Nephritis"
Ram Raj Singh, M.D.
Professor of Medicine & Pathology
University of California, Los Angeles
Although systemic lupus erythematosus (SLE) affects women much more frequently than men, men with SLE experience more severe organ damage. The goal of the current proposal is to investigate the contribution of sex chromosomes in increased organ damage in males with SLE. Studies over the last 30 years have focused on the role of sex hormones in conferring gender differences in SLE. However, extensive studies suggest that sex hormonal effects do not fully account for the profound gender differences seen in SLE. This Project uses a unique model system that will allow investigators to understand the role of sex chromosomes in the absence of confounding effects of sex hormones. These unique strains have been created in a way that mice with both XX and XY sex chromosomes have ovaries. Analogously, strains have been created where mice with both XX and XY chromosomes have testes. The investigators will also evaluate the effect of a gene on X chromosome that might contribute to increased organ damage in males with SLE. The results of the proposed study will not only aid our understanding of lupus, but will also potentially lead to identification of newer targets of treatment.
"Immunologic Actions of Glycosaminoglycans in Cutaneous Lupus"
Victoria Werth, M.D.
Chief of Dermatology
University of Pennsylvania, School of Medicine
Skin lupus can be very disfiguring, and yet the cause of the inflammation leading to redness and scarring is poorly understood. The immune system is set up to respond to various insults, such as bacteria, and sugars on bacteria can trigger immune reactions as part of a normal response to infection. Recently, it has become clear that there are naturally occurring sugars in the skin that can be altered, and these can activate the immune system. One of these sugars, hyaluronic acid, accumulates in the skin in patients with many forms of skin lupus. This hyaluronic acid is split into small fragments by ultraviolet light. It has been shown that this fragmented hyaluronic acid can bind to receptors on the inflammatory cells in the skin, thus activating the cells and increasing the inflammation seen in the skin in lupus. There are also other sugars that are increased in the skin of patients with skin lupus, particularly in discoid lupus, and these have just recently been characterized by our immunostaining studies. Their role in lupus is completely unknown. Recent scientific developments now permit better and more specific studies about the exact reason for the increased sugars seen in the skin, as well as the role of these sugars in the inflammatory cascade of skin lupus. It is likely that they represent a very early trigger of skin disease.