Role of NLRP3 signals in ischemia/reperfusion-induced organ injury

Project Summary: This proposal evaluates how the cytoplasmic innate immune receptor, NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) contributes to chronic kidney disease (CKD) after SARS-CoV2 infection of human and murine kidneys. The project is highly significant for understanding the steps leading to chronic renal injury associated with COVID-19 disease. Broad/long-term objectives: The long-term goals of the proposed research are to define how activation of NLRP3 contributes to chronic injurious tissue responses in human kidneys following SARS-CoV2 infection. Specific Aims: The central goal of this proposal is to test the hypothesis that SARS-CoV2 infection triggers cell- type specific responses that affect the NLRP3 pathway, and that dysregulation of this pathway contributes to the pathogenesis of CKD as a post-acute sequalae of COVID-19 disease. Research Design and Methods for Achieving the Stated Goals: Aim 1 will examine the effect of SARS-CoV2 infection on NLRP3 pathway activation and its functional consequences in human and murine renal tubular epithelia and will test consequences of blockade. Aim 2 will examine how SARS-CoV2 infection induces chronic kidney injury using two murine models of infection, and tests whether blockade of NLRP3 signaling pathways prevents that injury. Aim 3 will examine the consequences of NLRP3 pathway activation and blockade in SARS-CoV2 chronically infected human kidney organoids. Health Relatedness of Project: If the aims of this proposal are met we will learn how activation of NLRP3 contributes to the pathogenesis of the post-acute sequalae of CKD after COVID-19 disease. This knowledge is crucial for the development of rational target therapies for prevention or amelioration of organ injury following SARS- CoV2 infection.