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

LSUHSC COBRE：项目 3：SRNS 中慢性炎症*引起的 T 细胞信号转导

• 批准号: 7382265
• 负责人: DIEGO H AVILES
• 金额: $ 19.76万
• 依托单位: LSU HEALTH SCIENCES CENTER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7382265
• 关键词: LSUHSC; COBRE; PROJ; CELL; SIGNAL

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.

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。慢性炎症引起的T细胞信号转导的改变：激素抵抗型特发性肾病综合征(SRINS)是儿童和成人肾功能衰竭和终末期肾病(ESRD)的重要原因。它约占儿童终末期肾病的15%，其发病率还在上升，原因不明。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和激素敏感型特发性肾病综合征(SSINS)的发病机制中发挥主要作用。类固醇耐药的机制尚不清楚。申请人的初步研究表明，SRINS患者的T细胞IL-2的表达和产生增加，NFkB-P65的选择性降低。这些结果是相关的，因为核因子-DB可以减少T细胞的凋亡，增加IL-2的产生，从而激活STAT-5。反过来，STATS可以与糖皮质激素受体(OCR)结合，阻止其核转位，从而导致类固醇抵抗。因此，我们的初步数据支持这样的假设：“SRINS患者具有损害GCR核转位并导致类固醇耐药的信号转导机制的特定改变。拟议的项目将确定这些改变在SRINS患者中的频率，并测试两种可以解释类固醇耐药发生的机制。申请者将使用患者样本和新的体外模型来完成拟议的工作。