# Cellular Engineering to identify gasdermin protein networks regulating inflammatory cell death

> **NIH NIH P01** · CASE WESTERN RESERVE UNIVERSITY · 2020 · $427,816

## Abstract

Abstract
Infectious bacteria and inflammatory insults can be so toxic to an organism that they require an immediate
response. One such response, called pyroptosis, causes an inflammatory cell death that both alerts the
immune system to the immediate threat and also ensures a continued inflammatory effort. In classical
pyroptosis, Caspase-1 or Caspase-11 (Caspase-4/5 human) cleaves the pore forming protein, Gasdermin D
(GSDMD). This cleaved GSDMD then oligomerizes to form a pore in cellular membranes. Gasdermin D pore
formation allows the acute release of IL-1 from the cell, while also destroying membrane integrity such that
mitochondrial damage and electrolyte imbalances quickly kill the cell. Implicit in this is that should pyroptosis
be blocked, either genetically or pharmacologically, neutralization of the pathogen is so important to
organismal survival that alternative mechanisms to initiate cytokine release and inflammatory cell death must
have evolved. We are only now beginning to understand these compensatory responses and their role in
shaping the immune response. Our preliminary data, with support from the preliminary data from the other
three projects in this PPG application, will establish that mechanisms of compensation involve both Gasdermin
redundancy and alternative protease cleavage events. We hypothesize that these compensatory mechanisms
are cell-type specific. We further posit that they influence the timing and amplitude of cytokine release, the
timing and inflammatory capacity of the resulting cell death and the in vivo immune response to inflammatory
stimuli. The overall hypothesis of this application is that mechanisms to compensate for loss of pyroptosis
alter the inflammatory and immunologic response to an inflammatory insult. We further hypothesize that this
compensation helps establish myeloid cell homeostasis and that disruption of these compensatory
mechanisms influences the pathologic development of Myelodysplasia and subsequent Leukemia progression.
The long-term goal of this work is to better understand how pyroptotic compensatory mechanisms influence
the inflammatory response and immunologic homeostasis in hopes of better understanding how to manipulate
these pathways in disease.

## Key facts

- **NIH application ID:** 10024452
- **Project number:** 1P01AI141350-01A1
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** Derek W Abbott
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $427,816
- **Award type:** 1
- **Project period:** 2020-07-24 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10024452

## Citation

> US National Institutes of Health, RePORTER application 10024452, Cellular Engineering to identify gasdermin protein networks regulating inflammatory cell death (1P01AI141350-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10024452. Licensed CC0.

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