This new round of grants brings the total of research projects supported by the LRI to 42, the largest number of lupus scientists supported by private sector funding. LRI-funded grants include 28 devoted to novel research or brand new scientific hypotheses and methodologies, and 14 for Fellowship and Career Development awards, programs which are helping to build the pipeline of qualified scientists who will continue the progress in understanding and treating lupus.
"We were extremely pleased with the high caliber of novel research grant submissions we received from both established and new investigators, many of which have the potential to characterize biomarkers or predictors to identify patients with accelerating disease activity, and others which seek to identify new therapies," said Peter Lipsky, MD, scientific director, National Institute of Arthritis and Musculoskeletal and Skin Diseases, NIH. "We expect that many of these will generate solid new hypotheses that will go on to receive additional funding from the NIH as was the case with the first round of LRI grants which received more than $7 million in extended funding."
Dr. Lipsky, who co-chaired the Peer Review Committee with Ann Marshak-Rothstein, Ph.D., professor of microbiology at Boston University School of Medicine, organized one of the most rigorous peer review systems to review the grant applications, with 20 of the top lupus researchers around the country participating.
The scientists who were awarded $225,000 grants are:
- Roberto Caricchio, MD, University of Pennsylvania, Philadelphia
APOPTOTIC NUCLEOSOMAL DNA AND ITS RELEVANCE IN SLE. Dr. Caricchio's research focuses on an important autoantigen in lupus, called nucleosome. Recent evidence suggests that nucleosomes are derived from a process called programmed cell death or apoptosis, and that such process may be the primary supplier of autoantigens for SLE, making apoptosis a potentially robust therapeutic target. This study aims to confirm the exact role that apoptotic nucleosomes play in the cause of SLE and pinpoint the source of this dangerous material. This work may provide a stronger rationale for targeting new therapies at apoptotic nucleosome. - Robert M. Clancy, PhD, New York University School of Medicine, Hospital for Joint Diseases, New York
CIRCULATING ENDOTHELIAL CELLS, A BIOMARKER TO PREDICT SUBCLINICAL ATHEROSCLEROSIS IN PATIENTS WITH SLE. Dr. Clancy's research project will examine the relationship between circulating endothelial cells and the onset of atherosclerosis in lupus. These cells are activated by immune stimuli and are potential participants in the inflammatory process that contributes to tissue damage and atherosclerosis. Using a large patient base, Dr. Clancy's study will test this intriguing idea which could lead to a new therapy. - Mary K. Crow, MD, Hospital for Special Surgery, New York
BIOMARKERS OF DISEASE FLARE IN SLE. A previous LRI grant recipient, Dr. Crow will examine several new candidate biomarkers that may reflect lupus flares. One set of potential biomarkers includes interleukin 8 (IL-8) and the interleukin 8 receptor. The second potential biomarker is an uncharacterized gene product with sequence similarity to regulators of RNA processing. Confirmation of either of these candidate genes will give us the ability to predict lupus flare and will advance testing of new therapies in patients. - Anne Davidson, MD, Albert Einstein College of Medicine, New York
BIOMARKERS FOR RENAL REMISSION IN SLE. The goal of Dr. Davidson's study is to use real-time PCR and microarray technology to develop a clinical biomarker in lupus nephritis. The researchers will identify inflammatory molecules in the kidneys and urine that are associated with remission and relapse, and will use this information to study the urine of patients entering a clinical trial of a new therapeutic regimen for lupus nephritis. - Umesh S. Deshmukh, PhD, University of Virginia, Charlottesville
ROLE OF KIDNEY ANTIGEN REACTIVE T CELLS IN THE PATHOGENESIS OF LUPUS GLOMERULONEPHRITIS. Dr. Deshmukh's research will investigate whether antibodies are always the basis of kidney disease in lupus, or whether there are other populations of T cells that can trigger the disease process, a very important question for the lupus community. He will also determine whether there is a relationship between the patient's gender and the progression of lupus to kidney disease. - Bevra H. Hahn, MD, UCLA Medical School, Los Angeles
PRO-INFLAMMATORY HIGH DENSITY LIPOPROTEINS AS A BIOMARKER FOR RISK FOR ATHEROSCLEROSIS IN SLE. Dr. Hahn, collaborating with a cardiology group at UCLA, has found abnormal HDL cholesterol in some lupus patients, which promotes the oxidation of low density fats (OxLDL), leading to atherosclerosis. The LRI grant will allow Dr. Hahn to explore the abnormalities in HDL in lupus patients and determine their correlations with disease manifestations. Her research may lead to a new test for pro-inflammatory HDL to identify lupus patients at risk for atherosclerosis. - V. Michael Holers, MD, University of Colorado Health Sciences Center, University of Colorado School of Medicine, Denver
COMPLEMENT RECEPTOR 2 AS A DNA RECEPTOR. Dr. Holers and colleagues are attempting to determine the importance of a newly discovered binding protein that tightly interacts with DNA in the disease process. In this study, researchers will examine how this protein receptor binds with DNA and whether dysfunctional DNA binding is an important factor in triggering lupus. - Elahna Paul, MD, PhD, Massachusetts General Hospital, Harvard Medical School, Boston
IMMUNO/RENAL INTERFACE IN MURINE LUPUS GLOMERULONEPHRITIS. By studying a mouse model of lupus glomerulonephritis, Dr. Paul will learn how kidney cells react to an autoimmune attack. She will examine early kidney lesions before clinical signs of the disease are present, with the goal of predicting the development of kidney disease in lupus patients. - David S. Pisetsky, MD, PhD, Duke University Medical Center, Durham
ROLE O HMGB1 (HIGH MOBILITY GROUP PROTEIN) IN THE PATHOGENESIS OF SLE. Dr. Pisetsky's research will focus on a protein called HMGB1 that serves two functions in the body. Inside the cell, HMGB1 exists in the cell nucleus and binds DNA. Outside the cell, HMGB1 stimulates inflammation. Dr. Pisetsky will determine the process by which this protein is released into the blood when cells die and the mechanisms by which HMGB1 can stimulate an autoimmune response, and then he will determine whether HMGB1 may serve as a biomarker for lupus because of its association with inflammation and cell death. In addition, this work will uncover whether HMGB1 can be a target of therapy. - Luminita Pricop, MD, Hospital for Special Surgery, New York
GENETIC AND ACQUIRED MODIFIERS OF APC FUNCTION IN SLE. Dr. Pricop's extremely novel research concept focuses on the role of inhibitory Fc receptors, a gene associated with lupus, in stimulating B and T cells. Her investigations will look at the mechanism that leads immune complexes to stimulate B and T cells, which could characterize new genetic markers for lupus. - Chander Raman, PhD, University of Alabama at Birmingham
CD5: A NOVEL TARGET FOR TREATMENT OF SLE. Dr. Raman's research is focused on targeting CD5, a novel target for treatment in lupus. Lupus is characterized by the presence of autoreactive T lymphocytes which activate autoreactive B lymphocytes and promote development and progression of the disease. The laboratory has recently made the novel discovery that the molecule CD5, expressed on all T-cells, is a key regulator of survival. The researchers propose that blocking the signal of CD5 will promote cell death of autoreactive T-cells, a potential target for therapy. - Robert A.S. Roubey, MD, University of North Carolina at Chapel Hill
BIOMARKERS OF HYPERCOAGULABILITY IN SLE AND APS (ANTIPHOSPHOLIPID SYNDROME). Dr. Roubey's study will investigate the mechanisms of blood clotting in antiphospholipid syndrome (APS), a condition present in one-third of lupus patients that can lead to strokes, heart attacks and pregnancy loss. Researchers will use novel approaches to measure tissue factor activity to explain why some lupus patients tend to develop clots, and will assess whether newly developed blood tests can serve as a biomarker to identify the patients at risk for this condition. - Robert Winchester, MD, Columbia University College of Physicans and Surgeons, New York
IDENTIFICATION OF BIOMARKERS IN CIRCULATING LEUKOCYTE SUBPOPULATIONS THAT IDENTIFY EVENTS IN THE MOLECULAR PATHOGENESIS OF SLE NEPHRITIS. The study seeks to identify biomarkers in circulating blood cells that predict the presence and clinical significance of either of two different patterns of lupus renal glomerular injury and inflammation recently identified in work by Dr. Karin Peterson and colleagues. One patient subset had a milder form of proliferative nephritis with interferon-induced genes suggesting the entrance of activated NK cells. A contrasting subset with more fibrosis had evidence of B cells, T cells and activated macrophages of dendritic cells.
"By bringing new minds and new eyes to solving the perplexing challenges we face in lupus, the LRI is moving closer each day toward prevention, improved therapies and a cure for lupus," said William Paul, MD, chief of the Laboratory of Immunology of the National Institute of Allergy and Infectious Diseases at the NIH who serves as Chairman of the LRI Scientific Advisory Board.
Lupus affects 1-1.5 million Americans and is a leading cause of kidney disease, stroke and cardiovascular disease in young women. Currently available treatments are often toxic, and there hasn't been a new drug approved for lupus in 40 years. The Lupus Research Institute is leading the advancement of new science to prevent, treat and cure lupus. More information about the Lupus Research Institute is available at www.lupusresearchinstitute.org.