LSUHSC COBRE:PROJ 3: T CELL SIGNAL TRANSDUCT*CAUSED BY CHRONIC INFLAMMAT*IN SRNS

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。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。所列机构为中心机构，不一定为研究者机构。SRNS中慢性炎症引起的T细胞信号转导的改变：类固醇耐药特发性肾病综合征（SRINS）是儿童和成人肾衰竭和终末期肾病（ESRD）的重要原因。它约占儿童ESRD的15%，并且由于未知原因，发病率正在上升。除了少数具有podocin突变的患者外，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）的发病机制中的主要作用。类固醇耐药的机制尚不清楚。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表达和产生以及NF κ B-p65的选择性降低。这些结果是相关的，因为NF-DB可以减少T细胞凋亡并增加IL-2的产生，从而激活STAT 5。反过来，STATS可以结合糖皮质激素受体（OCR），防止其核转位，并导致类固醇耐药性。因此，我们的初步数据支持这一假设，即“SRINS患者的信号转导机制发生了特异性改变，损害了GCR的核转位并导致类固醇耐药。拟议的项目将确定SRINS患者中这些改变的频率，并测试可以解释类固醇耐药性发展的两种机制。申请人将使用患者样本和新型体外模型完成拟定工作。

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. Alterations in T cell signal transduction caused by chronic inflammation in SRNS: Steroid-resistant idiopathic nephrotic syndrome (SRINS) is an important cause of renal failure and end-stage renal disease (ESRD) in children and adults. It accounts for approximately 15% of ESRD in children and, for unknown reason the incidence is rising. Apart from a minority of patients who have podocin mutations, strong evidence supports a primary role for T cells in the pathogenesis of both SRINS and steroid-sensitive idiopathic nephrotic syndrome (SSINS). The mechanisms for steroid resistance are unknown. The applicant's preliminary studies have shown that T cells from SRINS patients have an increased expression and production of IL-2 and a selective decrease in NFkB-p65. These results are relevant since NF-DB can decrease T cell apoptosis and increase IL-2 production, which activates STAT 5. In turn STATS can bind the glucocorticoid receptor (OCR) preventing its nuclear translocation and resulting in steroid resistance. Thus our preliminary data support the hypothesis that "patients with SRINS have specific alterations in signal transduction mechanisms that impair the nuclear translocation of GCR and lead to steroid resistance. The proposed project will determine the frequency of these alterations in patients with SRINS, and test two mechanisms that could explain the development of steroid resistance. The applicant will use patient samples and novel in vitro models to accomplish the proposed work.