Targeting NLRP3 inflammasome for treating muscle complications of chronic kidney disease

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SUMMARY(Scope of Work) The cachexia/wasting syndrome in children with chronic kidney disease (CKD) consists of anorexia, reduced body and muscle mass, poor nutrition and short stature, and has been clearly associated with increased mortality risk. Our preliminary data show that blocking interleukin (IL)-Beta is most successful at reversing cachexia, pointing toward a pathogenic role for the NLRP3 inflammasome. The overarching goal of this research is to develop novel therapy of the muscle wasting complication of CKD by further understanding of NLRP3 signaling in its pathophysiology. Hypothesis: NLRP3 inflammasome signaling is a key driver of CKD comorbidities of cachexia, and muscle wasting through specific and targetable pathways. We employ two established CKD mouse models, 5/6 nephrectomy and the cystinosis knockout (Ctns[-/-]-) mouse. To test this hypothesis, we propose the following aim: To elucidate the role of the NLRP3 inflammasome signaling pathway in the pathophysiology and as a target for novel therapy of CKD cachexia. We will study the temporal sequence of NLRP3 signature in peripheral blood mononuclear cells (PBMCs), fat and muscle in CKD associated cachexia. We will extend this investigation to children with CKD to see if NLRP3 signature in PBMCs is a surrogate for fat and muscle expression. We will use a myeloid specific NLRP3 knockout model to study the role of circulating myeloid cells. Finally, we will investigate the impact of pharmacologic blockade of NLRP3 using CRID3(MCC950) and of IL-1Beta using anakinra on CKD cachexia. Completion of our aim will fulfill an unmet clinical need leading to improvement in long- term outcomes.