Systemic Lupus Erythematosus (SLE) is an autoimmune disease of unknown etiliology, characterized by aberrant T cell function which contributes to disease pathology. T cells once activated, have elevated levels of CD40L and decreased levels of interleukin-2 (IL-2). Elevated CD40L expression provides help to B cells while decreased IL-2 prevents proper regulation of the immune response. The underlying reasons for this abnormality remain elusive. Finding key molecules that regulate T cell function in SLE will lead to the design of appropriate biomarkers and more specific treatment modalities. This proposal aims at the career development of Dr. Kyttaris as an independent translational investigator in SLE. During the years of award, Dr. Kyttaris will investigate the expression and cooperation between nuclear factor of activated T cells (NFAT) and activator protein-1 (AP-1) in T cell function in SLE. Beth Israel Deaconess Medical Center will provide an ideal clinical, educational and research environment for Dr. Kyttaris to conduct under the guidance of two accomplished mentors his research and develop into an independent investigator. Dr. Kyttaris will attend courses and interact with experts in the fields of basic immunology, systemic autoimmunity, clinical rheumatology, biostatistics and epidemiology. The study proposed herein is a cross- sectional case-control study of patients with SLE. The preliminary results that form the basis for this proposal showed that SLE T cells once activated, have increased NFAT and decreased AP-1 activity;in turn this leads to increased CD40L and decreased interleukin (IL)-2 expression. In the three aims analyzed Dr. Kyttaris will compare the expression of NFAT and AP-1 in T cells from patients with SLE and controls confirming the preliminary data and ascertaining the effect of disease activity in the expression of these molecules. Thereafter, Dr. Kyttaris will elucidate the underlying mechanisms for the differential expression of these two transcription factors in SLE. Finally he will apply novel techniques to correct the aberrant expression of NFAT/AP-1 on gene transcription. In conclusion, the results of these studies will help us better understand how the SLE T cells respond to stimulation, identify potential targets for therapy and molecules that can be used as biomarkers.
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