This proposal describes a 5-year training program to develop a researcher with an academic career into an independent investigator. The PI has completed a Medical Scientist Training Program leading to a dual M.D.-Ph.D. degree, followed by Dermatology residency in at NYU School of Medicine and is currently a research fellow in the Training Program in Autoimmunity at Beth Israel Deaconess Medical Center (BIDMC). The proposal outlined for this mentored research program is to expand the PI's knowledge in the field of autoimmune disease research while extending his technical skills, with the ultimate goal of achieving independence as a researcher. The K23 mechanism is appropriate for this goal and also in a mentored environment serves to aid the transition of the PI's field of experience in HIV immunology to the current field of interest in lupus. Under the career development plan outlined in this proposal, the PI will devote 75% of his full-time effort to research and didactic activities, and the remaining 25% of his time in his clinical duties as an attending physician in dermatology, a necessary function for this patient-oriented research. The program will involve the study of autoimmunity, immunology, cell signaling, and specifically systemic lupus erythematosus. The PI's scientific development will be mentored by Jean-Pierre Kinet, M.D. and co-mentored by George Tsokos, M.D. Dr. Kinet is a recognized leader in allergy and inflammation, having elucidated mechanisms of mast cell signaling and identified Calcium-Release-Activated Calcium Channel Modulator 1 (CRACM1) as a key cell membrane pore responsible for calcium flux. He is a Professor of Pathology at Harvard Medical School and Director of the Division of Allergy and Immunology at BIDMC. Dr. Tsokos is also recognized as a leader in lupus research, having identified multiple mechanisms of immunopathogenesis and T cell signaling abnormalities in lupus. He is a Professor of Medicine at Harvard Medical School, Chief of the Rheumatology Division at BIDMC, and Program Director for the Training Program in Autoimmunity at BIDMC. The program will also enlist the expertise of Su-Jean Seo M.D., Ph.D., and Steven Tahan, M.D. Dr. Seo is an Instructor in Pathology at Harvard Medical School and dermatopathologist at BIDMC. Dr. Tahan is an Associate Professor of Pathology at Harvard Medical School and Chief of Dermatopathology at BIDMC. The training and research environment will also be facilitated by Robert Stern, M.D. and Michael Bigby, M.D. Dr. Stern is the Carl J. Herzog Professor of Dermatology at Harvard Medical School and Chairman of Dermatology at BIDMC. He has helped the PI set up a lupus specialty clinic at BIDMC for the clinical component of the program which can facilitate patient recruitment. He also specializes in psoriasis and has done numerous clinical studies of this disease. Dr. Bigby is an Associate Professor of Dermatology at Harvard Medical School and is a senior attending physician at BIDMC. He has a clinical focus in lupus and will serve as the clinical advisor to the PI in the management of the disease. Numerous studies have examined immunopathogenic mechanisms of lupus, including aberration in calcium signaling in activated T cells, which involves multiple molecular components. The recent identification of Calcium-Release-Activated Calcium Channel Modulator 1 (CRACM1), which forms a selective cell membrane pore, was determined to be responsible for permitting extracellular calcium influx to signal gene transcription for T cell activation. The research project will investigate the role of CRACM1 in abnormal calcium signaling in T cells of patients of lupus.
The specific aims are to: 1) determine CRACM1 expression in T cells of lupus patients, compare them with T cells of healthy controls and patients with the control disease psoriatic arthritis, and determine the subpopulations involved, 2) determine the contribution of CRACM1 to the increased calcium flux seen in T cells of lupus patients with functional studies using CRACM inhibitors, and 3) assess whether the role of CRACM1 in this pathogenic model extends to a target organ of lupus, namely skin, by examining CRACM1 expression in T cells of inflammatory infiltrates in lupus skin.
These aims will investigate CRACM1's role in the pathogenesis of lupus and whether it could potentially be a therapeutic target. To evaluate if T cells of lupus patients demonstrate increased CRACM1 expression compared to controls, T cells will be stained with fluorescently labeled anti-CRACM1 antibodies and then analyzed by flow cytometry. Immunophenotyping will also determine which subpopulations of T cells may be expressing CRACM1. Then to determine whether CRACM1 expression accounts for the increased calcium flux in lupus T cells, the T cells will be treated with CRACM1 inhibitors to see if the heightened calcium levels are reduced to levels found in normal T cells;ratios of free and bound calcium to a fluorescent dye will be measured to determine calcium levels. Finally, to determine whether increased CRACM1 expression are also found in skin as a target organ, CRACM1 will be stained in infiltrates of lupus skin biopsies and compared to controls. The Pathology Department of BIDMC provides an ideal setting for training physician-scientists by drawing expertise from diverse resources, and in coordination with the Rheumatology Division and the Dermatology Department, customizes a career development strategy and research plan that will promote the development of the PI into an independent investigator in translational research.

Public Health Relevance

Systemic lupus erythematosus is a disease in which the immune system attacks the body's own organ systems, and there are many abnormal mechanisms in the immune system by which this occurs, one example being that immune cells called T cells have abnormal function. One known abnormality in T cells of lupus patients is how calcium levels change in them for their function, and the molecule we are studying called Calcium-Release-Activated Calcium Channel Modulator 1 (CRACM1), may contribute to these abnormal levels in lupus T cells. If CRACM1 is involved in the abnormal T cell function, then perhaps this molecule can be used to aid in diagnosing patients or targeted by new medications to treat lupus.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Mentored Patient-Oriented Research Career Development Award (K23)
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Arthritis and Musculoskeletal and Skin Diseases Special Grants Review Committee (AMS)
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Mancini, Marie
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Beth Israel Deaconess Medical Center
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