NFAT/AP-1 cooperation in SLE T cells

描述(申请人提供)：系统性红斑狼疮(SLE)是一种自身免疫性疾病，其特征是T细胞功能异常，导致疾病病理。T细胞一旦激活，CD40L水平升高，白细胞介素2(IL-2)水平下降。CD40L的高表达为B细胞提供了帮助，而IL-2的降低阻碍了免疫反应的适当调节。这种反常现象的根本原因仍然难以捉摸。寻找调节SLE中T细胞功能的关键分子将导致设计合适的生物标记物和更具体的治疗方式。这项提议旨在将Kyttaris博士作为SLE的独立翻译调查员的职业发展。在获奖的几年中，Kyttaris博士将研究活化T细胞核因子(NFAT)和激活蛋白-1(AP-1)在SLE T细胞功能中的表达和协同作用。贝丝以色列女执事医疗中心将为Kyttaris博士提供一个理想的临床、教育和研究环境，让他在两位成就卓著的导师的指导下进行他的研究，并发展成为一名独立的研究员。Kyttaris博士将参加基础免疫学、系统自身免疫、临床风湿学、生物统计学和流行病学领域的课程并与专家互动。本研究是关于系统性红斑狼疮患者的横断面病例对照研究。形成这一建议基础的初步结果表明，SLE T细胞一旦激活，NFAT增加，AP-1活性降低；反过来，这会导致CD40L增加，IL-2表达减少。在分析的三个目标中，Kyttaris博士将比较NFAT和AP-1在SLE患者和对照组T细胞中的表达，确认初步数据，并确定疾病活动对这些分子表达的影响。此后，Kyttaris博士将阐明这两种转录因子在SLE中差异表达的潜在机制。最后，他将应用新技术来纠正基因转录中NFAT/AP-1的异常表达。综上所述，这些研究结果将有助于我们更好地了解SLE T细胞对刺激的反应，确定潜在的治疗靶点和可用作生物标志物的分子。

DESCRIPTION (provided by applicant): 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.