# The role of serpins and LRP1 in the esophageal epithelium during eosinophilic esophagitis

> **NIH NIH R01** · CINCINNATI CHILDRENS HOSP MED CTR · 2024 · $543,150

## Abstract

PROJECT SUMMRAY
Eosinophilic esophagitis (EoE) is a chronic allergic disease of the esophagus, partly mediated by type 2 immunity
and epithelial dysfunction. Patients with EoE suffer from dysphagia, pain, and the lowest quality of life among
children with chronic, pediatric conditions. The epithelium is the first line of defense against potential threats,
providing a physical barrier between the host and the external environment. The site where the barrier breach
occurs may be a location where normally harmless antigens encounter immune cells and potentially lead to
production of danger signals, priming a break in immune tolerance and initiation of allergic responses.
Understanding the physiologic factors that preserve/restore esophageal homeostasis will facilitate our long-term
goal of developing improved therapies with long-lasting effects and a cure for EoE.
The sharp edge between intact barrier versus barrier breach is orchestrated by proteases and protease
inhibitors. We demonstrated that losing an epithelial protease inhibitor or altering proteolytic activity provide a
paramount signal in the development of EoE. Delivery of the serine protease inhibitor A1AT reversed EoE
phenotypes (e.g., barrier function, type 2 mediator production) in vitro and in an EoE mouse model.
We have now revealed another variable in the protease-inhibitor equation; the low-density lipoprotein receptor–
related protein 1 (LRP1). LRP1 is a scavenger receptor that mediates endocytosis and elimination of ligands,
including serine protease inhibitors (serpins) in complex with proteases. Interaction of a serpin with a protease,
exposes encrypt motifs in the serpin’s sequence that interact with LRP1 and serve as LRP1 agonists. Following
the binding of a serpin-protease complex to LRP1, LRP1 initiates signaling pathways that terminate inflammatory
responses and promote epithelial homeostasis. We demonstrated that LRP1 agonists potently reverse EoE
disease in vitro and in vivo. In addition, we showed that an intracellular truncated LRP1 fragment appears
exclusively in EoE biopsies. The function of the truncated LRP1 fragment in EoE biopsies is unknown. We
hypothesize that excessive LRP1 processing during EoE promotes transcriptional changes that propagate EoE.
In this study, we will explore the mechanism of action by which serpins and synthetic LRP1 agonists promote
inflammatory resolution in vitro and in vivo. We developed an experimental platform to investigate the function
of full-length serpins, serpin-derived peptides with LRP1 binding motifs, and small molecule inhibitors that inhibit
proteolytic activity but lack LRP1 binding motifs. Our unique experimental framework enables us to test serpin
functions that are independent of protease inhibition. We will elucidate the downstream functional consequences
of LRP1 processing in esophageal epithelial cells and investigate the enzymes responsible for LRP1 processing.
Successful completion of this study will provide fundam...

## Key facts

- **NIH application ID:** 10882006
- **Project number:** 1R01DK136512-01A1
- **Recipient organization:** CINCINNATI CHILDRENS HOSP MED CTR
- **Principal Investigator:** Nurit P AZOUZ
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $543,150
- **Award type:** 1
- **Project period:** 2024-06-01 → 2029-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10882006

## Citation

> US National Institutes of Health, RePORTER application 10882006, The role of serpins and LRP1 in the esophageal epithelium during eosinophilic esophagitis (1R01DK136512-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10882006. Licensed CC0.

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