# Function and regulation of constitutive protein translation in platelets

> **NIH NIH R01** · THOMAS JEFFERSON UNIVERSITY · 2024 · $390,000

## Abstract

Project Summary
 The goals of this proposal are: 1) to elucidate the molecular signaling of protein translation initiation in
circulating human platelets and characterize the plasma growth factor- or hormone-driven pathways, map the
regenerating human platelet proteome, and determine the roles of constitutive translation in platelet functional
reactivity; 2) to determine the roles of ARGONAUTE2 (AGO2, Ago2 in mice) in platelet mRNA, microRNA
(miRNA) and protein expression, platelet reactivity, and the specific roles of platelet miRNA-mediated
suppression of translation in hemostasis and thrombotic potential. The studies in this proposal will elucidate
essential concepts of the molecular physiology of platelet function. In addition, these studies will have profound
implications for two areas of widespread clinical significance: alterations in growth factor/hormone
homeostasis, and current use and development of pharmacological inhibitors of translation in disease
treatment. Surprisingly little attention has been paid to roles of translation in so-called “resting” platelets in
circulation, following the overall presumption that translation is of limited importance. In prior studies of
“resting” platelet translation, ex vivo platelets were removed from their native plasma environment, and
translation steadily came to a halt. We interpret these prior studies to suggest instead that platelets undergo
translation constitutively in the presence of plasma, e.g., in circulation, and that this expenditure of molecular
resources and cellular energetics is critical for platelet protein homeostasis and functionality. Our strong
preliminary data support this hypothesis and we propose a series of innovative approaches to investigate this
poorly understood aspect of platelet biology and its functional outcomes. We have shown for the first time that
platelets in circulation undergo constitutive translation of a robust proteome due to translation initiation
signaling driven by plasma-borne growth factors and hormones, that this process is modulated by platelet
miRNAs and AGO2, and that constitutive miRNA-modulated translation in platelets regulates platelet function.
We will pursue an array of innovative approaches to test the following hypotheses: Aim 1- 1) “resting” platelets
in circulation are translationally active due to ongoing signaling initiated by plasma growth factors and
hormones; 2) constitutive translation driven by plasma growth factors maintains platelet protein homeostasis
necessary for hemostatic function; Aim 2 - 1) abundant miRNAs and Ago2-mediated RNA inhibition in platelets
modulate constitutive translation driven by plasma growth factors and hormones; 2) Ago2/miRNA-mediated
suppression maintains platelets in a reactive state necessary to support hemostasis while limiting thrombosis.
Together, the outcomes of these studies will significantly expand our understanding of control of platelet
function, hemostasis and thrombosis, as well as implica...

## Key facts

- **NIH application ID:** 10843949
- **Project number:** 5R01HL159006-04
- **Recipient organization:** THOMAS JEFFERSON UNIVERSITY
- **Principal Investigator:** Lawrence E Goldfinger
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $390,000
- **Award type:** 5
- **Project period:** 2021-09-01 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10843949

## Citation

> US National Institutes of Health, RePORTER application 10843949, Function and regulation of constitutive protein translation in platelets (5R01HL159006-04). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10843949. Licensed CC0.

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