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

> **NIH NIH R01** · SCRIPPS RESEARCH INSTITUTE, THE · 2024 · $382,272

## Abstract

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 activ...

## Key facts

- **NIH application ID:** 10853086
- **Project number:** 5R01DK128547-04
- **Recipient organization:** SCRIPPS RESEARCH INSTITUTE, THE
- **Principal Investigator:** Dianne B Mckay
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $382,272
- **Award type:** 5
- **Project period:** 2021-09-24 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10853086

## Citation

> US National Institutes of Health, RePORTER application 10853086, Role of NLRP3 signals in ischemia/reperfusion-induced organ injury (5R01DK128547-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10853086. Licensed CC0.

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