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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Mentored Patient-Oriented Research Career Development Award (K23)
Project #
5K23AR055672-05
Application #
8315918
Study Section
Arthritis and Musculoskeletal and Skin Diseases Special Grants Review Committee (AMS)
Program Officer
Mancini, Marie
Project Start
2008-09-11
Project End
2013-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
5
Fiscal Year
2012
Total Cost
$97,637
Indirect Cost
$7,232
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02215
Markopoulou, Anastasia; Kyttaris, Vasileios C (2013) Small molecules in the treatment of systemic lupus erythematosus. Clin Immunol 148:359-68
Kyttaris, Vasileios C; Kampagianni, Ourania; Tsokos, George C (2013) Treatment with anti-interleukin 23 antibody ameliorates disease in lupus-prone mice. Biomed Res Int 2013:861028
Kyttaris, Vasileios C (2012) Targeting B cells in severe thrombotic thrombocytopenic purpura--a road to cure? Crit Care Med 40:317-8
Ghosh, Debjani; Tsokos, George C; Kyttaris, Vasileios C (2012) c-Jun and Ets2 proteins regulate expression of spleen tyrosine kinase in T cells. J Biol Chem 287:11833-41
Hedrich, Christian M; Rauen, Thomas; Kis-Toth, Katalin et al. (2012) cAMP-responsive element modulator ? (CREM?) suppresses IL-17F protein expression in T lymphocytes from patients with systemic lupus erythematosus (SLE). J Biol Chem 287:4715-25
Chatterjee, Madhumouli; Rauen, Thomas; Kis-Toth, Katalin et al. (2012) Increased expression of SLAM receptors SLAMF3 and SLAMF6 in systemic lupus erythematosus T lymphocytes promotes Th17 differentiation. J Immunol 188:1206-12
Kyttaris, Vasileios C; Tsokos, George C (2011) Targeting lymphocyte signaling pathways as a therapeutic approach to systemic lupus erythematosus. Curr Opin Rheumatol 23:449-53
Ghiran, Ionita C; Zeidel, Mark L; Shevkoplyas, Sergey S et al. (2011) Systemic lupus erythematosus serum deposits C4d on red blood cells, decreases red blood cell membrane deformability, and promotes nitric oxide production. Arthritis Rheum 63:503-12
Kyttaris, Vasileios C; Zhang, Zheng; Kampagianni, Ourania et al. (2011) Calcium signaling in systemic lupus erythematosus T cells: a treatment target. Arthritis Rheum 63:2058-66
Juang, Y-T; Peoples, C; Kafri, R et al. (2011) A systemic lupus erythematosus gene expression array in disease diagnosis and classification: a preliminary report. Lupus 20:243-9

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