# Regulation of Protein C Pathways

> **NIH NIH R01** · SCRIPPS RESEARCH INSTITUTE, THE · 2021 · $944,019

## Abstract

Activated protein C (APC) is a naturally occurring plasma serine protease that has been translated to the clinic
as a recombinant wild type or mutant biologic. In a diverse collection of preclinical animal injury models,
pharmacologic APC provides benefits. APC not only has anticoagulant activity but also initiates cell signaling
via multiple receptors, in particular via several protease activated receptors (PAR). APC-initiated cell signaling
contributes to tissue homeostasis and host defense systems. Beneficial APC-initiated biased signaling is caused
by specific cleavages of PAR1 and PAR3, and it also can be triggered by APC binding to Tie2 on endothelial
cells. Despite recent insights, there is a major gap in knowledge about protein-protein interactions (PPI) between
APC and its cellular receptors. Aim 1 studies will use a library of 28 recombinant APC mutants to provide a
database regarding APC's receptor specificities which will then enable engineering of APC mutants with
receptor-specific selectivity, e.g., an APC mutant with highly selective PAR1-specific or PAR3-specific signaling
capabilities. Such receptor-selective APC mutants will be useful reagents for deciphering which receptors play
critical roles on cells in vitro or in animals in vivo, and they may lead to translation for novel APC mutants. One
major anti-inflammatory mechanism for APC is its recently discovered ability to inhibit NLRP3 inflammasome
activation. There a major need for understanding how APC inhibits inflammasome activation, and Aim 2 studies
will provide highly novel new knowledge. When APC is generated in excess relative to thrombin generation,
increased risk for bleeding arises. This may potentially occur in hemophilia or during use of direct oral
anticoagulant (DOAC). Aim 3 studies will provide new knowledge about bleeding and joint damage in murine
hemophilia models linked to relatively excessive APC and will determine whether various strategies may reduce
joint damage that arises due to bleeding in hemophilic joints. The proposed studies will provide novel mechanistic
insights and new APC variants which may aid translation related to the APC pathways.

## Key facts

- **NIH application ID:** 10131252
- **Project number:** 5R01HL142975-04
- **Recipient organization:** SCRIPPS RESEARCH INSTITUTE, THE
- **Principal Investigator:** JOHN H GRIFFIN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $944,019
- **Award type:** 5
- **Project period:** 2018-06-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10131252

## Citation

> US National Institutes of Health, RePORTER application 10131252, Regulation of Protein C Pathways (5R01HL142975-04). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10131252. Licensed CC0.

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