# Biased PAR1 Agonism in Sickle Cell Disease

> **NIH NIH R01** · UNIV OF NORTH CAROLINA CHAPEL HILL · 2022 · $388,750

## Abstract

PROJECT SUMMARY
Title: Biased PAR1 Agonism in Sickle Cell Disease
Sickle cell disease (SCD) is caused by a single nucleotide mutation in the β-globin gene, resulting in
altered red cell physiology that drives chronic hemolytic anemia and painful vaso-occlusive crisis (VOC)
triggered by microvascular occlusion/stasis. VOC is the leading cause of hospitalizations of sickle cell
patients. Activation of the main thrombin receptor, protease activated receptor 1 (PAR1), enhances the
interactions between endothelial cells and sickle RBCs. In my recently published study, I demonstrated
that PAR1 deficiency on nonhematopoietic cells or inhibition of PAR1 with vorapaxar attenuates
microvascular stasis in a mouse model of SCD. In addition to thrombin, PAR1 is also activated by
activated protein C (APC). The APC-mediated activation of PAR1 is referred to as “biased agonism”
because it activates a different signaling pathway than thrombin and ultimately induces cytoprotective
and anti-inflammatory effects. My central hypothesis is that canonical thrombin/PAR1 signaling
contributes to microvascular stasis whereas non-canonical APC/PAR1 signaling reduces microvascular
stasis and thromboinflammation. I hypothesize that inducing beneficial PAR1 biased signaling will be
advantageous compared to complete PAR1 inhibition, which blocks the deleterious thrombin-
dependent signaling as well as beneficial APC signaling. In the first aim I will compare the roles of
thrombin/PAR1 and APC/PAR1 signaling on coagulation, inflammation, and microvascular stasis in
sickle cell mice using mice with PAR1 point mutations that select for activation by either thrombin or
APC. In the second aim, I will compare the therapeutic potential of a signaling-selective form of APC,
3K3A-APC, to two inhibitors of PAR1, parmodulin 2 and vorapaxar, on inflammation, microvascular
stasis, and acute chest syndrome. Finally, in the third aim, I will investigate the effects of biased PAR1
agonism on mortality and end-organ damage in sickle mice. These studies will investigate the role of
biased PAR1 signaling in the pathology of SCD.

## Key facts

- **NIH application ID:** 10327643
- **Project number:** 5R01HL155193-02
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **Principal Investigator:** Erica M Sparkenbaugh
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $388,750
- **Award type:** 5
- **Project period:** 2021-01-10 → 2025-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10327643

## Citation

> US National Institutes of Health, RePORTER application 10327643, Biased PAR1 Agonism in Sickle Cell Disease (5R01HL155193-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10327643. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*