# Innate Inflammatory Control of Cachexia

> **NIH NIH R35** · UNIVERSITY OF VIRGINIA · 2024 · $394,478

## Abstract

Project Summary
Cachexia, or the inflammatory loss of lean body mass, is a leading predictor of morbidity across chronic diseases.
A disease of complex etiology, cachexia has proven difficult to model in animals. Little is known regarding the
molecular mechanisms controlling cachexia onset, persistence and pathology; and widely efficacious
interventions to reverse cachexia are lacking. We have recently shown that Toxoplasma infection in mice is
novel animal model to study sustained cachexia. The longevity of this model has led to the discovery that
chronically cachectic mice have perivascular fibrosis in the liver. Importantly, we have found that mice defective
in the IL-1 innate immune signaling pathway are protected from cachexia and fibrosis and altered lipid
metabolism, despite harboring a similar titer of Toxoplasma as WT animals. We hypothesize that cachexia is
a cost of long-term IL-1 signaling. In this proposal we will determine whether eliminating chronic infection or
blocking fibrosis is sufficient to reverse cachexia. We will identify the IL-1R expressing cell types driving cachexia
and determine how IL-1 signaling on fibroblasts and/or endothelial cells control aberrant lipid metabolism in
cachectic livers. Our studies are timely, as a recent clinical study demonstrated that blocking human IL-1a with
a monoclonal antibody has reversed some symptoms of cachexia. Thus, we have a novel model to understand
the mechanism of IL-1 function in cachexia and test therapeutic interventions for disease reversal. Understanding
the role of the IL-1 axis in cachexia will improve the life span and comfort of patients suffering from a wide range
of debilitating chronic diseases.

## Key facts

- **NIH application ID:** 10845517
- **Project number:** 5R35GM138381-05
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** Sarah E. Ewald
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $394,478
- **Award type:** 5
- **Project period:** 2020-08-01 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10845517

## Citation

> US National Institutes of Health, RePORTER application 10845517, Innate Inflammatory Control of Cachexia (5R35GM138381-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10845517. Licensed CC0.

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