# Innate Immune signal transduction specificity in inflammatory disease

> **NIH NIH R35** · CASE WESTERN RESERVE UNIVERSITY · 2024 · $402,500

## Abstract

ABSTRACT
The NOD2:RIPK2 complex helps a cell recognize and respond to an intracellular bacterial infection. Activation
of this pathway initiates a cytokine response that helps tailor the adaptive immune system to eradicate the
offending pathogen. Signaling from this complex must be precisely tailored. Too little inflammation can cause
immunodeficiency that can manifest in dysbiosis while too much inflammation can manifest in inflammatory
disease. Over the past decade, my lab has worked to understand this signaling system with the goal of
identifying drug targets such that when the NOD2:RIPK2 complex is hyperactive and therefore
hyperinflammatory, we have pharmacologic tools to inhibit it. To this end, we have now developed agents for
RIPK2 that inhibit its kinase activity. These inhibitors are now at the Pre-IND stage and we anticipate filing for
an IND in late 2020 or early 2021. Despite this chemical success, key questions surrounding RIPK2’s kinase
activity remain. While some studies suggest that kinase activity is necessary for function, others suggest it is
not. We don’t know the kinase-dependent versus kinase-independent signaling pathways that are activated or
inhibited. We don’t know any bone fide RIPK2 substrates, and we don’t know which patients will particularly
benefit from RIPK2 inhibition. To this end, we have developed phosphoproteomic and phospho-substrate
databases utilizing mass spectrometry and chemical genetics. This grant application aims to leverage these
unpublished databases to i) identify novel RIPK2 substrates, ii) identify novel RIPK2 kinase-regulated signaling
pathways and iii) identify patient populations in which RIPK2 targeting might be most efficacious. Better
understanding RIPK2’s kinase activity is highly significant as RIPK2 inhibitors enter the clinic over the next few
years.

## Key facts

- **NIH application ID:** 10689014
- **Project number:** 5R35GM141603-03
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** Derek W Abbott
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $402,500
- **Award type:** 5
- **Project period:** 2021-05-01 → 2027-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10689014

## Citation

> US National Institutes of Health, RePORTER application 10689014, Innate Immune signal transduction specificity in inflammatory disease (5R35GM141603-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10689014. Licensed CC0.

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