# Coordination of inflammatory signaling and cardiac fibrosis by small proline rich proteins

> **NIH NIH R01** · UNIVERSITY OF ROCHESTER · 2022 · $425,246

## Abstract

PROJECT SUMMARY
Cardiac fibroblasts (CF) contribute to the inflammatory response and subsequent scar formation following
myocardial infarction (MI); however, the mechanisms coordinating these processes are poorly understood. Using
mouse models and human heart tissue, we have found that Small proline rich proteins (Sprr) are uniquely
expressed in CF, and are among the most upregulated genes during disease. Conversely, Sprr gene expression
is extinguished in CF during exercise. Our preliminary data reveals that SPRR2B binds USP7 and regulates
USP7 / MDM2 - E3 ubiquitin ligase substrate selection, facilitating p53 ubiquitination and degradation and
relieving constraints on CF accumulation in disease. In contrast, SPRR1A harbors an interaction motif for tumor
necrosis factor (TNF) receptor-associated factor (TRAF)-2, an E3 ubiquitin ligase that controls inflammatory
signaling. Based on our preliminary data and supporting literature, we hypothesize that context dependent
control of E3 ubiquitin-ligase substrate selection by SPRR1A and SPRR2B modulates the inflammatory
response following an ischemic event and drives the accumulation of pathological CF, which results in
cardiac fibrosis and the progression of HF. A corollary to this hypothesis is that novel MDM2-E3 ubiquitin
ligase antagonists, currently in clinical trials as anti-cancer agents, may be useful for the treatment of cardiac
fibrosis. Here, we propose the following aims to define a transcriptional paradigm of CF gene regulation in health
and disease, and elucidate a novel and druggable mechanism of E3 ubiquitin ligase substrate selection in CF
that coordinates the inflammatory response and the development of cardiac fibrosis. If successful, the proposed
experiments will refine our understanding of the molecular mechanisms that drive cardiac fibrosis and the
progression of HF. Our study may also uncover a novel mechanism of ubiquitin-mediated protein degradation
that is broadly applicable to the fields of cardiology, progenitor cell-based therapeutics, and cancer biology and
further efforts to harness novel E3-ubiquitin ligase antagonists for therapeutic benefit.

## Key facts

- **NIH application ID:** 10305604
- **Project number:** 5R01HL144867-04
- **Recipient organization:** UNIVERSITY OF ROCHESTER
- **Principal Investigator:** Eric M Small
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $425,246
- **Award type:** 5
- **Project period:** 2018-12-21 → 2023-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10305604

## Citation

> US National Institutes of Health, RePORTER application 10305604, Coordination of inflammatory signaling and cardiac fibrosis by small proline rich proteins (5R01HL144867-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10305604. Licensed CC0.

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