# ICAM-1 targeted thrombomodulin: an experimental therapeutic for the Acute Respiratory Distress Syndrome

> **NIH NIH K08** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2020 · $132,300

## Abstract

Project Summary/Abstract
 The Acute Respiratory Distress Syndrome (ARDS) is a major health concern that affects 200,000
patients a year and kills ~40% of the patients affected. Currently, there are no pharmacologic agents that
improve outcome. Patients often present to the Emergency Room relatively early in the course of the
illness, suggesting that lung injury might be prevented or even reversed, given timely administration of safe
and effective therapeutics. As a practicing Emergency Physician, this clinical experience has motivated me
to dedicate my career to the development and translation of biotechnology for the early diagnosis,
prognostication, and treatment of ARDS. The current project involves a novel therapeutic approach, which
provides protection in a mouse model of lung injury, and proposes three specific aims to further define its
mechanism of action and advance its pre-clinical development.
 In ARDS, there is a reduction in the amount of Thrombomodulin (TM) expressed on the surface of
pulmonary endothelial cells. This proteins normally partners with the Endothelial Protein Receptor (EPCR)
to activate protein C, which in turn helps to mitigate inflammation, reduce plasma protein leak, and prevent
microvessel thrombosis. The therapeutics described in the proposal augment this natural protective
mechanism by binding to ICAM-1, an endothelial cell adhesion molecule upregulated in the setting of
inflammation, and anchoring recombinant TM to the cell surface. Previous work demonstrates that this
approach enables partnering of the targeted therapeutic with naturally expressed EPCR, boosting protein C
activation and reducing the severity of lung injury when used prophylactically in a mouse model of ARDS.
 In the first specific aim, a series of in vitro microfluidic experiments are proposed to: 1. model the
complex interactions which occur at the interface of flowing human blood and activated lung endothelium,
and 2. clarify how ICAM-targeted TM works to reduce coagulation, immune cell adhesion, and vascular
barrier dysfunction in these models. In the second aim, the synthesis and testing of a second generation of
ICAM-targeted therapeutics is proposed, with the hypothesis that the new formulation will improve
pharmacokinetics and prolong functional activity in the lung. In the third aim, extensive testing of ICAM-
targeted TM is proposed in two distinct murine models of ARDS, to determine efficacy, dosing, therapeutic
time window, safety, and mechanism of action.

## Key facts

- **NIH application ID:** 10002272
- **Project number:** 5K08HL130430-05
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** Colin Fred Greineder
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $132,300
- **Award type:** 5
- **Project period:** 2016-09-01 → 2021-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10002272

## Citation

> US National Institutes of Health, RePORTER application 10002272, ICAM-1 targeted thrombomodulin: an experimental therapeutic for the Acute Respiratory Distress Syndrome (5K08HL130430-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10002272. Licensed CC0.

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