ALTERNATIONS IN T CELL SIGNAL TRANSDUCTION CAUSED BY INFLAMMATION IN SRNS

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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.