# The role in inflammation in platelet activation and thrombosis

> **NIH NIH K08** · UNIVERSITY OF COLORADO DENVER · 2020 · $162,043

## Abstract

Project Summary
My primary hypothesis is that GAS6/MERTK signaling is upregulated in the setting of inflammation, leading to
enhanced platelet activation responses, increased platelet-leukocyte interactions, and subsequent thrombosis.
Therefore, we believe inhibition of this pathway will decrease thromboinflammation. MERTK is a receptor
tyrosine kinase expressed on the platelet surface that, when stimulated by its plasma-based ligand GAS6,
leads to augmentation of platelet activation responses. I have shown that inhibition of this signaling axis, either
by anti-MERTK small molecule inhibitor (UNC2025) or a novel soluble MERTK splice variant (iMer) decreases
in vitro platelet activation in functional assays and in vivo thrombosis in murine models. I also recently
demonstrated that plasma GAS6 levels were elevated in children with thrombosis compared to healthy
controls, suggesting that GAS6 may also mediate thrombosis (potentially through its ability to bridge
membrane-bound phosphatidylserine and MERTK).
In this proposed project, I will rigorously investigate the role of inflammation in platelet activation and
thrombosis, as well as the specific mechanisms by which inhibition of GAS6/MERTK signaling impacts
thromboinflammation. Though I already have a strong research base in platelet activation response assays
and murine models of thrombosis, this proposal provides the experimental skills and knowledge base needed
to evaluate the contributions of the inflammatory system in this particular context. This additional training will
allow me to continue developing as a physician-scientist and execute the transition to an independent basic-
translational research career in thromboinflammation.
Herein, I propose three specific aims to 1) characterize the effect of inflammation upon GAS6/MERTK
signaling and subsequent platelet activation in vitro and thrombosis in vivo, 2) define the mechanism through
which GAS6/MERTK signaling impacts thromboinflammation, and 3) determine the role of iMer in regulating
GAS6/MERTK signaling in platelets.
My mentorship team consists of recognized leaders in functional assays of platelet activation and murine
models of thrombosis (Dr. Jorge Di Paola, primary mentor), and cell-cell interactions in the setting of
inflammation (Dr. Sean Colgan, co-mentor). The training plan clearly outlines how I will advance my research
career development by building upon my previous studies and experience using the proposed research aims,
didactic course-work, attendance at local and national meeting, and guidance from my mentorship team and
scholarship oversight committee. I specifically designed the proposed project and associated career
development plan to facilitate my transition to independent investigator with the long-term goal of developing
novel strategies to decrease inflammation-related thrombosis.

## Key facts

- **NIH application ID:** 9892726
- **Project number:** 1K08HL146941-01A1
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** BRIAN R BRANCHFORD
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $162,043
- **Award type:** 1
- **Project period:** 2020-01-08 → 2020-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9892726

## Citation

> US National Institutes of Health, RePORTER application 9892726, The role in inflammation in platelet activation and thrombosis (1K08HL146941-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9892726. Licensed CC0.

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