ALTERNATIONS IN T CELL SIGNAL TRANSDUCTION CAUSED BY INFLAMMATION IN SRNS

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 激素抵抗型特发性肾病综合征(SRINS)是儿童终末期肾病的主要原因。有强有力的证据支持T细胞在SRINS和激素敏感型特发性肾病综合征(SSINS)的发病机制中的作用。申请者的初步研究表明，SRINS患者的T细胞IL-2表达增加，而NF-kB p65表达选择性降低。这是因为核因子-kB p65的表达减少可以减少T细胞的凋亡，增加IL-2的产生。我们的Jurkat T细胞体外模型显示，沉默NF-kB p65会导致类固醇耐药。目前，我们正在研究糖皮质激素受体(GCR)和STAT5在类固醇耐药中的作用。我们的初步数据支持这一假说，即SRINS患者存在损害GCR核转位并导致类固醇耐药的信号转导机制的特定改变。为了检验这一假设，我们提出了以下具体目标： 1.确定SRINS与SSINS患者T细胞改变的频率。 探讨核因子-kB和IL-2在SRINS患者中的表达基因多态性。 2.验证核因子-kB p65缺失与SRINS T细胞GCR核移植受损有关的假设 A.在患者的T细胞中证明这一现象。 B.建立体外模型以检验分子机制。 3.验证SRINS中IL-2活性增加与STAT_5产生增加和GCR-STAT_5复合体形成增加有关的假设。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Steroid-resistant idiopathic nephrotic syndrome (SRINS) is a primary cause for end stage renal disease in children. There is strong evidence supporting the role of T cells in the pathogenesis of SRINS and steroid sensitive idiopathic nephrotic syndrome (SSINS). The applicant preliminary studies have shown that T cells from SRINS patients have an increased expression of IL-2 and a selective decrease in NF-kB p65. This is relevant since decreased expression of NF-kB p65 can decrease T cell apoptosis an increase IL-2 production. Our in vitro model with jurkat T cells showed that silencing NF-kB p65 results in steroid resistance. Currently we are studying the role of the glucocorticoid receptor (GCR) and STAT5 in steroid resistance. Our preliminary data support the hypothesis that patients with SRINS have specific alterations in signal transduction mechanism that impair nuclear translocation of GCR and lead to steroid resistance. To test the hypothesis we propose the following specific aims: 1. Determine the frequency of alterations in T cells from patients with SRINS vs. SSINS. Evaluate the expression gene polymorphism for NF-kB and IL-2 in patients with SRINS. 2. To test the hypothesis that the absence of NF-kB p65 is associated with impaired nuclear transfer of of the GCR in T cells from SRINS a. Demonstrate this phenomenom in T cells from patients. b. Develop an in vitro model to test molecular mechanism. 3. Test the hypothesis that increased IL-2 activity in SRINS is associated with increased STAT 5production and increased formation of GCR-STAT 5 complexes.