Sunday, May 11, 2025
5/11/2025
Role of NLRP3 signals in ischemia/reperfusion-induced organ injury - Project Summary: This proposal evaluates how intracellular signaling pathways generated by the cytoplasmic innate immune receptor NLRP3 are regulated in renal tubular epithelial cells. Renal tubule epithelial cells play a central role in ischemic kidney injury, and our lab and others have shown that global NLRP3 blockade can prevent experimental renal ischemia/reperfusion injury. NLRP3 signaling classically results in cell death (pyroptosis), however alternative NLRP3 signaling pathways have recently been identified that lead to secretion of IL1b/IL18 without cell death. Thus, selectively targeting NLRP3-mediated cell death signaling might prevent renal tubule injury while still preserving the host’s ability to secrete IL1b/IL18 and mount needed host defense responses (e.g., antimicrobial responses). The project is highly significant for the development of targeted therapeutics for ischemic kidney injury, which occurs frequently in hospitalized patients and in all organs procured for transplantation. Broad/long-term objectives: The long-term goals of the proposed research are to define how NLRP3 contributes to injurious tissue responses in the kidney and how its signaling can be effectively and selectively targeted. Specific Aims: The specific objective of this proposal is to test the hypothesis that the cytoplasmic pattern recognition receptor NLRP3 can be specifically targeted in renal tubular epithelial cells to selectively block NLRP3-mediated renal tubule cell death, while preserving IL1b/IL18 responses. Aim 1 defines the mechanisms that drive NLRP3 signaling pathways in proximal renal tubule cells. Aim 2 determines how NLRP3 signaling can be selectively targeted in the proximal renal tubule cells. Aim 3 determines how NLRP3 signaling, and its selective blockade, influences renal tubular injury/IL1b/IL18 secretion in vivo, when NLRP3 expression is isolated to the renal tubule epithelium. Research Design and Methods for Achieving the Stated Goals: Aim 1 compares and contrasts activation of NLRP3 in human and murine proximal renal tubular cells and will determine how NLRP3 activation contributes to pyroptosis and/or production of IL1b/IL18. Aim 2 will determine how specific NLRP3 activation pathways can be targeted in the two species to prevent cell death and preserve cytokine secretion. Aim 3 will focus on understanding how NLRP3 restricted to the renal tubule epithelium in vivo can be targeted to prevent renal tubular injury without impairing IL1b/IL18. In the third aim, two different models of NLRP3 expression will be used; one where the renal tubules express a conditional loss-of-function of NLRP3 and another where there is a hyper-activatable form of NLRP3. The studies here will determine whether canonical NLRP3-mediated cell death signaling can be uncoupled from noncanonical signaling to prevent cell death while preserving secretion of IL1b/IL18. Health Relatedness of Project: If the aims of this proposal are met, we will learn how activation of NLRP3 (deemed a central cellular stress detector) can be regulated to target a common disease, renal ischemia/reperfusion injury. This knowledge is crucial for the development of rational targeted therapies for prevention or amelioration of renal ischemia/reperfusion injury in clinical situations where hypoxia is anticipated.
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