# Innate Immune Signal Transduction Specificity in Inflammatory Disease

> **NIH NIH R01** · CASE WESTERN RESERVE UNIVERSITY · 2020 · $343,252

## Abstract

Abstract:
Innate immune signaling requires careful coordination such that the adaptive immune system can be tailored to
eradicate an offending pathogen. Too much signaling can result in autoinflammatory disease while too little
signaling can result in immunodeficiency. Interestingly, immunodeficiency is often complicated by hyper-
inflammatory states, and the maintenance of this inflammatory balance is particularly important in the
intracellular pathogen recognition signaling system driven by the NOD2:RIPK2 complex. Loss-of-function
polymorphisms in NOD2 cause decreased signaling in response to bacterial infection and predispose to
Crohn’s disease, a disorder characterized by acute and chronic inflammation of the gastrointestinal tract. In
contrast, gain-of-function NOD2 mutations, which cause increased signaling in response to bacterial infection,
cause Early Onset Sarcoidosis, an inflammatory disorder characterized by uveitis and granulomatous
inflammation in the mediastinum. Even WT NOD2 and WT RIPK2 influence inflammatory disease. As NF-B
regulated genes, NOD2 and RIPK2 expression and activity is heightened during inflammation, and
hyperactivation of WT NOD2 and WT RIPK2 can drive the pathophysiology of diseases as diverse as multiple
sclerosis, rheumatoid arthritis, asthma and inflammatory bowel disease. This therefore highlights the unique
balance that must be maintained by both NOD2 and RIPK2 to maintain physiologic inflammation while
avoiding pathologic inflammation. Our work under this grant has been directed at understanding the molecular
basis for NOD2:RIPK2 signal transduction and to translate that work to clinical medicine. In the current grant
application, we aim to study the interaction of the inflammasome’s interaction with the NOD2:RIPK2 signaling
pathway, the ubiquitin dynamics regulating this pathway and a novel mechanism of downregulation of this
pathway.

## Key facts

- **NIH application ID:** 9988659
- **Project number:** 2R01GM086550-11A1
- **Recipient organization:** CASE WESTERN RESERVE UNIVERSITY
- **Principal Investigator:** Derek W Abbott
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $343,252
- **Award type:** 2
- **Project period:** 2008-12-09 → 2021-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9988659

## Citation

> US National Institutes of Health, RePORTER application 9988659, Innate Immune Signal Transduction Specificity in Inflammatory Disease (2R01GM086550-11A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9988659. Licensed CC0.

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