# Translational Control of Megakaryocyte and Platelet Function in Sepsis

> **NIH NIH R01** · UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH · 2021 · $381,250

## Abstract

Summary/Abstract
Regulation of gene expression at the translational level (i.e., mRNA-protein) is poorly understood in normal
megakaryocytes, and it is virtually unknown if inflammatory diseases alter translational responses in
megakaryocytes and platelets. With that said, inflammation contributes to the pathogenesis of numerous
diseases such as sepsis, and inflammatory agonists are considered potent triggers of mRNA translation. This
grant proposal will utilize human and mouse model systems (in vitro and in vivo) and state-of-the-art
sequencing (ribosomal footprinting and eIF4E-enrichment) to determine how translational control pathways
regulate megakaryocyte and platelet gene expression – in the setting of health and septic situations.
Preliminary data supporting this project demonstrates that the mammalian target of rapamycin (mTOR) and the
MAP kinase-interacting serine/threonine-protein kinase 1 (MNK1), two translational control pathways that
converge on the initiation step of translation, regulate protein synthetic events and functions in megakaryocytes
and platelets. These preliminary results have led to the hypothesis that the septic milieu will
significantly modify mTOR and/or MNK1-dependent translation in megakaryocytes and platelets,
resulting in inappropriate formation and function of platelets during the course of sepsis. Specific
Aim1 will test the hypothesis that inflammatory agonists generated during sepsis will alter protein synthetic
events in megakaryocytes and the formation of platelets in an mTOR and MNK1-dependent manner. Specific
Aim 2 will determine how genetic deletion of mTOR or MNK1 regulates the ex vivo and in vivo function of
platelets in the presence or absence of inflammation. Specific Aim 3 will test the hypothesis that the septic
milieu activates the mTOR and/or MNK1 signaling pathways and thereby increases protein synthesis by
platelets. It will also determine if deletion of mTor and/or Mnk1 in mouse platelets leads to adverse outcomes
in murine models of sepsis. Successful completion of these aims will 1) identify translated mRNAs in
megakaryocytes that are under mTOR and/or MNK1-dependent control and whether these translational
signaling pathways regulate the final steps of platelet production, 2) delineate the effects of mTOR and MNK1
on functions of megakaryocytes and platelets in health and inflammation, 3) characterize inadvertent side-
effects of clinically-used mTOR and MNK1 inhibitors on megakaryocytes and platelets, and 4) determine if
mTOR or MNK1 in megakaryocytes and platelets regulate outcomes in models of sepsis. Data generated will
immediately increase our understanding of how translational control pathways alter megakaryocyte and
platelet functions in the setting of sepsis.

## Key facts

- **NIH application ID:** 10210293
- **Project number:** 5R01HL142804-04
- **Recipient organization:** UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH
- **Principal Investigator:** Matthew Thomas Rondina
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $381,250
- **Award type:** 5
- **Project period:** 2018-07-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10210293

## Citation

> US National Institutes of Health, RePORTER application 10210293, Translational Control of Megakaryocyte and Platelet Function in Sepsis (5R01HL142804-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10210293. Licensed CC0.

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