# Glycoprotein Ib in vascular biology and host defense

> **NIH NIH R01** · SCRIPPS RESEARCH INSTITUTE, THE · 2020 · $566,955

## Abstract

Project summary
Our goal is to understand novel functions of the platelet glycoprotein (GP) Ib-IX-V complex, a key receptor for
several ligands mediating, among others, adhesive interactions (mostly through von Willebrand factor), cell-cell
contacts (interacting with leukocyte integrin αMβ2 and P-selectin) and coagulation (binding several coagulation
factors including thrombin). With this project we intend to extend the understanding of GPIb physiopathologic
relevance beyond megakaryocyte/platelet domains and more firmly into the area of innate immune mecha-
nisms. Nonetheless, von Willebrand factor (VWF) and thrombin, key GPIb partners in hemostasis and throm-
bosis, remain the main ligands of interest for the proposed new studies. In our work over nearly 30 years we
have contributed to establish the bases for understanding how VWF, thrombin and GPIbα, the main subunit in
the GPIbIX-V complex, interact. With respect to thrombin, even with the structure of the GPIbα-thrombin com-
plex unveiled at atomic level detail, elucidating dependent functions has remained elusive. With the knowledge
acquired through past studies and the ensuing generation of mice lacking thrombin-GPIb binding on platelets,
and stimulated by surprising preliminary results obtained using these models, we propose two articulated spe-
cific aims to develop a project addressing unexpected new functions. In aim 1 we will extend the effort to define
the physiopathological significance of thrombin binding to platelet GPIbα developing two sub-aims. In the first,
we will explore the functional roles of the newly identified high and low affinity thrombin-GPIbα binding modes,
using for the purpose a mouse strain expressing a mutant human GPIbα (Y279F) in which high affinity throm-
bin binding is lost but low affinity is retained. In the second, we will address the problem posed by the se-
quence divergence between mouse and human GPIbα in the region of thrombin binding. We have identified
the residues of mouse GPIbα required for thrombin binding and propose to generate a mouse model with en-
dogenous mouse GPIbα selectively defective in thrombin binding but retaining all other ligand interactions with
intact species specificity. This will be an essential tool to ascertain the value for human physiopathology of
studying mechanisms of thrombin-induced platelet activation in mouse models with different PAR expression
on platelets. In aim 2 we will characterize expression and function of GPIbα on mast cells and its functional
role in anaphylaxis. We will develop two sub-aims. In the first we will characterize the structure of mast cell ex-
pressed GPIb in relation to the other components of the GPIb-IX-V complex. In the second we will explore
functions of mast cell expressed GPIbα evaluating roles in cell adhesion and in response to thrombin stimula-
tion. We have already generated several new mouse models with defective GPIb expression on mast cells.
The results of these studies will adva...

## Key facts

- **NIH application ID:** 9967091
- **Project number:** 5R01HL135294-04
- **Recipient organization:** SCRIPPS RESEARCH INSTITUTE, THE
- **Principal Investigator:** Zaverio M Ruggeri
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $566,955
- **Award type:** 5
- **Project period:** 2017-08-01 → 2021-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9967091

## Citation

> US National Institutes of Health, RePORTER application 9967091, Glycoprotein Ib in vascular biology and host defense (5R01HL135294-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9967091. Licensed CC0.

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