# Small GTPases in the biology of platelets and megakaryocytes

> **NIH NIH R35** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2020 · $623,573

## Abstract

ABSTRACT
Mammalian platelets are small anucleate blood cells specialized to continuously monitor and preserve the
integrity of the cardiovascular system (hemostasis). They are produced by megakaryocytes (MKs) in the bone
marrow and released into blood, where they circulate for ten days in humans and five days in mice until they
get cleared by phagocytes. Platelet homeostasis, i.e. the establishment of a defined peripheral platelet count,
requires tight regulation of both platelet production and clearance. To fulfill their hemostatic function, platelets
depend on a very sensitive signaling machinery that facilitates platelet adhesion under shear stress. This high
sensitivity, however, poses a risk for unwanted platelet activation that can lead to platelet clearance and/or
thrombosis. The overarching goal of our work is to achieve a better understanding of the molecular
mechanisms regulating MK development and platelet reactivity, with a specific focus on the role of small
GTPases in these processes. This R35 OIA application is an extension to three funded NHLBI R01 grants:
Small GTPases in Megakaryocyte Biology; Rap1 Signaling in Platelet Homeostasis and Vascular Hemostasis;
Spatial Regulation of Platelet Activation by Podoplanin-Clec2 Signaling. Our MK studies utilize unique
biosensors to establish a molecular signature of small GTPase activity (both Rho and Rap GTPases) during
the final stages of development, including the transition from proliferation to proplatelet formation. Once
established, we will establish proof-of-principle that precisely targeted perturbation of GTPase activity by
optogenetic tools is a viable strategy to optimize in vitro platelet production, a hot topic in Transfusion
Medicine. Our platelet work focuses more specifically on the role of Rap GTPases as master regulators of
cellular activation and hemostatic plug formation. We have utilized unique mouse models to establish the
importance and the key regulators of Rap1 signaling during platelet activation. Furthermore, we have shown
that Rap1 activity has to be tightly balanced both in quiescent, circulating and in hemostatically active platelets,
and that disturbance of this pathway leads to bleeding or thrombocytopenia/ thrombosis. In ongoing and future
work, we will expand on our cell biological and biochemical/-physical studies to provide a comprehensive
understanding of how Rap signaling controls platelet function, how it is regulated, and if/ how it contributes to
other patho-physiological processes such as vascular integrity in development/ inflammation and venous
thrombosis. We will use our unique biochemical assays to screen for inhibitors of Rap signaling. Our clinical
studies will investigate if Rap1 signaling is altered in various pathologies, and whether there is interindividual
variability in this pathway in healthy and diseased subjects? Together, these studies are expected to lead to
novel strategies for the diagnosis and management of some inherited and a...

## Key facts

- **NIH application ID:** 9899304
- **Project number:** 5R35HL144976-02
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Wolfgang Bergmeier
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $623,573
- **Award type:** 5
- **Project period:** 2019-03-21 → 2026-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9899304

## Citation

> US National Institutes of Health, RePORTER application 9899304, Small GTPases in the biology of platelets and megakaryocytes (5R35HL144976-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9899304. Licensed CC0.

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