# Regulation of the physiologic and pathologic activation of the NLRP3-inflammasome

> **NIH NIH R01** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2020 · $380,000

## Abstract

Abstract:
The inflammasome is a macromolecular complex that activates Caspase-1, a cysteine proteinase responsible
for processing several cytokines (IL-1β and IL-18) into active, mature forms that are released from cells. In
addition to cytokine processing, the inflammasome induces a novel cell death program with morphologic and
biochemical features of necrosis. The ATP-binding protein NLRP3 acts as a central scaffold during in the
assembly of some inflammasomes, termed NLRP3-inflammasomes. The NLRP3-inflammasome can be
activated by numerous Pathogen-Associated and host derived Damage-Associated Molecular Patterns
(PAMPs and DAMPs) as well as mutations in the ATP-binding domain that are associated with hereditary
periodic fever syndromes. The common molecular mechanisms that control NLRP3 ATP-binding and
inflammasome assembly in response to a wide variety of toxins have remained elusive. We have recently
demonstrated that NLRP3 binds directly to oxidized DNA, a molecule that has been implicated in activation of
NLRP3 by some stimuli. Preliminary data suggests binding accelerates the ATPase activity of NLRP3. We
now propose to study the molecular mechanisms of NLRP3 activation during physiologic and pathologic
activation states. We propose: 1) to determine the role oxidized DNA binding in the ATP binding cycle and
inflammasome assembly using in vitro reconstitution of the NLRP3-inflammasome and to define the DNA
binding domain of NLRP3. 2) to explore whether NLRP3 is activated by other oxidized polynucleotides
including RNA and DNA/RNA hybrids (which have also been implicated in NLRP3 activation) and identify the
polynucleotides that associate with NLRP3 when it is activated in cells by different physiologic and pathologic
stimuli. 3) to determine the role of NLRP3 phosphorylation in controlling oxidized DNA binding, ATPase
activity, and inflammasome assembly.

## Key facts

- **NIH application ID:** 9934970
- **Project number:** 5R01AI088255-10
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** JOSEPH A DUNCAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $380,000
- **Award type:** 5
- **Project period:** 2010-05-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9934970

## Citation

> US National Institutes of Health, RePORTER application 9934970, Regulation of the physiologic and pathologic activation of the NLRP3-inflammasome (5R01AI088255-10). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9934970. Licensed CC0.

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