# Transcriptional Outputs of the Necroptotic Pathway

> **NIH NIH R56** · UNIVERSITY OF WASHINGTON · 2024 · $350,000

## Abstract

Project Summary/Abstract
“Necroptosis” is a form of cell death with roles in host defense, autoimmunity, and cancer. Necroptosis is
associated with inflammation and immunity, but how cells in which the necroptotic pathway is active alter the
immune response is poorly understood. Much of the prior research in this area has focused on the role of lytic
cell death and the release of “DAMP” molecules in necroptosis-induced inflammation. However, recent work
from our group and others has highlighted key roles for proteins of the necroptotic pathway—including RIPK1
and TRIF—in activating inflammatory transcription programs, and has demonstrated that activation of
“necroptosis” can drive cytokine production in the absence of cell death in some settings. The work proposed
here will test the hypothesis that transcriptional signaling, not lytic cell death, represents the most
immunologically significant output of the “necroptotic” pathway, and that necroptotic cell death may actually
reduce inflammation by eliminating cells in which inflammatory transcription programs are active. To do this,
we will focus on thee Aims: First, we will define the interactions and transcription programs activated by
necroptotic pathway components in cultured cells, using engineered proteins and natural ligands. Second, we
will study the role of necroptosis pathway activation in vivo, by delivering engineered, constitutively active
forms of necroptosis inducers to the lung epithelium of mice. Third, we will evaluate the roles of necroptotic
transcription and cell death in the immune response to influenza A virus, a potent activator of the necroptotic
pathway. The work proposed here will use novel experimental tools to understand the immune response to
“necroptosis” in vivo. Given the emerging roles of this pathway in infection, autoimmunity and cancer, and the
substantial efforts underway to target it therapeutically, we suggest that these studies are timely and potentially
impactful.

## Key facts

- **NIH application ID:** 11125032
- **Project number:** 1R56AI179665-01A1
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** Andrew Atwell Oberst
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $350,000
- **Award type:** 1
- **Project period:** 2024-08-09 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11125032

## Citation

> US National Institutes of Health, RePORTER application 11125032, Transcriptional Outputs of the Necroptotic Pathway (1R56AI179665-01A1). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/11125032. Licensed CC0.

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