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.
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