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的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 激素抵抗性特发性肾病综合征（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和类固醇敏感性特发性肾病综合征（SSINS）发病机制中的作用。申请人的初步研究表明，来自SRINS患者的T细胞具有增加的IL-2表达和选择性降低的NF-κ B p65。这是相关的，因为NF-kB p65的表达降低可以减少T细胞凋亡，增加IL-2的产生。我们用Jurkat T细胞的体外模型显示沉默NF-κ B p65导致类固醇抗性。目前，我们正在研究糖皮质激素受体（GCR）和STAT 5在类固醇抵抗中的作用。我们的初步数据支持这一假设，SRINS患者有特定的信号转导机制的改变，损害GCR的核转位，导致类固醇耐药。为了检验这一假设，我们提出以下具体目标： 1. 确定SRINS与SSINS患者的T细胞变化频率。 评估SRINS患者NF-κ B和IL-2表达的基因多态性。 2. 为了检验以下假设，即NF-kB p65的缺失与SRINS的T细胞中GCR的核转移受损有关 a. 在患者的T细胞中证明这种现象。 B. 建立体外模型以测试分子机制。 3. 检验SRINS中IL-2活性增加与STAT 5产生增加和GCR-STAT 5复合物形成增加相关的假设。

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.