# Platelet Reprogramming During Inflammation

> **NIH VA I01** · VA SALT LAKE CITY HEALTHCARE SYSTEM · 2020 · —

## Abstract

Inflammation and sepsis is characterized by dysregulated host responses that span hemostatic, inflammatory,
and immune continuums. Thrombosis is a common complication of sepsis, contributing to adverse outcomes
including organ failure and death. The significance of this devastating dysregulated host response is
demonstrated by data suggesting half of all hospital deaths, including the Veterans population, may be attributed
to sepsis. Emerging evidence supports the concept that dysregulated platelet responses mediate the
pathophysiology during inflammation. Nevertheless, the molecular mechanisms and functional consequences of
dysregulated platelet functions during sepsis remain incompletely understood. Our proposal, entitled “Platelet
Reprograming During Inflammation” will identify new pathways by which inflammatory agonists including,
interferons (IFNs) regulate gene expression in platelets and their parent cell, the megakaryocyte (MK). Our
preliminary studies have identified that the expression of interferon-induced transmembrane protein 3 (IFITM3)
is robustly induced in human platelets during sepsis. Moreover, our data demonstrate that IFITM3 upregulates
fibrinogen endocytosis in MKs and platelets, leading to platelet hyperreactivity and thrombosis. The regulation
and function IFITM3 in MKs and platelets, or for that matter any other human cell, has never previously been
identified. In this proposal, we will leverage prospective clinical studies in sepsis with in vitro and in vivo murine
models. These complementary human and murine studies will allow us to demonstrate clinical relevance while
also dissecting the mechanisms by which IFITM3 governs MK and platelet function during inflammation. These
studies are translational and innovative as IFITM3 regulation of endocytosis, a process critical for
cellular function. This has not previously been studied in MKs, platelets, or – for that matter - primary
human cells. They will also determine for the first time whether inflammatory agonists regulate transcriptional
and translational events in MKs and developing platelets. This work will test an important functional
hypothesis and clarify pathophysiologic mechanisms of thrombosis during inflammation and sepsis.
This proposal has both immediate translational potential for the thousands of Veterans estimated to
develop sepsis, and will underlie additional progress for inflammatory diseases more broadly affecting
the Veteran population.

## Key facts

- **NIH application ID:** 9932310
- **Project number:** 5I01CX001696-03
- **Recipient organization:** VA SALT LAKE CITY HEALTHCARE SYSTEM
- **Principal Investigator:** Matthew Thomas Rondina
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2018-07-01 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9932310

## Citation

> US National Institutes of Health, RePORTER application 9932310, Platelet Reprogramming During Inflammation (5I01CX001696-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9932310. Licensed CC0.

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