# Contact Activation and Infection

> **NIH NIH R01** · OREGON HEALTH & SCIENCE UNIVERSITY · 2024 · $553,057

## Abstract

Project Summary
Our research project is designed to test our central hypothesis that the contact activation system
contributes to pathologic mechanisms that lead to vascular dysfunction, thrombin generation, and
inflammatory responses during systemic bacterial challenge by specific pathogens.
Despite the availability of effective antibiotics, sepsis remains a prevalent clinical syndrome and significant
cause of severe in-hospital morbidity and mortality, brought about by a sequence of rapidly advancing
dynamic molecular and cellular events that occur upon exposure to and subsequent systemic infection by
certain pathogens. Complicating the problem is the increasing prevalence of multiresistant bacterial
pathogens. At present, after more than half a century of research, drug development, and countless
clinical trials, there are still no FDA-approved marketed drugs specifically indicated for the treatment of
sepsis. Sepsis can lead to multiple organ system failure, including failure of vasoregulation, poor tissue
perfusion, edema, and systemic hypotension, which are hallmarks of severe sepsis. By triggering
cardiopulmonary and vascular collapse, it is often lethal even with available supportive and antibiotic
treatments. Sepsis may be accompanied by disseminated intravascular coagulation (DIC), which can lead
to both thrombosis and bleeding due to the consumptive coagulopathy. We focus on the contact activation
system, because 1) there appears to be a causal relationship between activation of coagulation factor XII
and the poor prognosis of some forms of sepsis, and 2) targeting the contact activation system as a
therapeutic approach is unlikely to have detrimental consequences for the host such as bleeding. We will
study the role of the molecular steps in the contact activation system in the development and outcome of
experimental bacterial infection, in vivo. We will define the roles of FXII (Aim 1) and its procoagulant
substrate FXI (Aim 2), and translate our mechanistic in vitro studies to characterize the pathological role of
contact activation in two distinct baboon models of bacterial infection.
The potential translational relevance of our project will be the identification of safe and druggable
molecular targets and mechanisms within the contact activation system. Our research may ultimately
provide rationale for the development of selective contact activation inhibitors that could safely benefit
patients that have or are at risk of infections by pathogens that can cause contact system activation.

## Key facts

- **NIH application ID:** 10903781
- **Project number:** 5R01AI157037-05
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** FLOREA LUPU
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $553,057
- **Award type:** 5
- **Project period:** 2020-09-23 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10903781

## Citation

> US National Institutes of Health, RePORTER application 10903781, Contact Activation and Infection (5R01AI157037-05). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10903781. Licensed CC0.

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