# Platelet Reprogramming During Inflammation

> **NIH VA I01** · VA SALT LAKE CITY HEALTHCARE SYSTEM · 2024 · —

## Abstract

Inflammation and sepsis are 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 these dysregulated host responses is demonstrated by
studies suggesting half of all hospital deaths, including Veterans, may be attributed to sepsis. Sepsis also
increases the long-term risk of cardiovascular disease and stroke, and causes substantial morbidity among
Veteran patients. Established and emerging evidence supports the concept that dysregulated platelet responses
mediate thrombotic events during inflammation, including sepsis. 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 interferon
alpha (IFN), which is systemically increased during sepsis, regulates the loading, trafficking, and secretion of
cargo proteins in platelets and their parent cell, megakaryocytes (MKs). We have identified that the expression
of interferon-induced transmembrane protein 3 (IFITM3) is robustly induced in platelets and MKs during
inflammatory stress. Our preliminary data also suggest that increased IFITM3 in platelets regulates the secretion
of cargo proteins to promote a thrombo-inflammatory milieu. In this proposal, we will perform complementary
clinical, ex vivo, and in vivo studies to determine how IFITM3 governs cargo loading, trafficking, and secretion in
platelets and MKs during inflammation. In specific aim 1, we will determine whether or not IFITM3 regulates
cargo granule secretion during inflammation and identify proteins that IFITM3 interacts with. We will also examine
the effects of a naturally-occurring, loss of function mutation in IFITM3 on secretion. In specific aim 2, we will use
complementary pharmacologic and genetic toolsets to determine if IFITM3 regulates cargo loading and
trafficking in platelet granules during inflammation. In specific aim 3, we will establish how IFITM3 participates in
inflammatory and thrombotic host responses during sepsis. These studies are innovative as IFITM3 has not
previously been identified as a regulator of cargo movement within platelets and MKs, or any other cell
for that matter. Regulated cargo movement is critical for proper cell functions and disrupted cargo
movement contributes to inflammation and thrombosis in many diseases. This work will therefore test an
important functional hypothesis and elucidate completely new pathophysiologic mechanisms of thrombosis
during inflammation and sepsis. This proposal will help us understand how interferons contribute to
sepsis-associated thrombosis (a disease affecting thousands of Veterans each year), and may elucidate
new therapeutic avenues to prevent these thrombotic complications. Discoveries made ...

## Key facts

- **NIH application ID:** 10579556
- **Project number:** 2I01CX001696-05A1
- **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:** 2024
- **Award amount:** —
- **Award type:** 2
- **Project period:** 2018-07-01 → 2026-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10579556

## Citation

> US National Institutes of Health, RePORTER application 10579556, Platelet Reprogramming During Inflammation (2I01CX001696-05A1). Retrieved via AI Analytics 2026-06-01 from https://api.ai-analytics.org/grant/nih/10579556. Licensed CC0.

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