# Oxidative stress in vaso-occlusion pathophysiology of sickle cell disease

> **NIH NIH K08** · OREGON HEALTH & SCIENCE UNIVERSITY · 2020 · $174,420

## Abstract

PROJECT SUMMARY
 Sickle cell disease (SCD) is the most common genetic hematologic disorder in the United States. The
pathophysiology of organ dysfunction in SCD extends beyond abnormal rheology and hemolysis, and includes
abnormal vascular function, thrombosis, and inflammation. There is increasing evidence that oxidative stress
is an important biochemical trigger for vaso-occlusion (VO) in SCD. Increased reactive oxygen species (ROS)
can lead to VO through platelet and leukocyte activation, and microvascular dysfunction. Whether
pharmacologic reduction in oxidative stress prevents VO and improves microvascular perfusion is not known.
The goal of this proposal is to use state-of-the-art microvascular perfusion and molecular imaging techniques
together with advanced plasma biochemical analysis to test mechanism and therapeutic impact of two
promising anti-oxidants implicated in reducing ROS in SCD: (a) N-acetylcystine (NAC), and (b) apocynin. In
Aim 1, the Townes murine model of SCD and control mice will be studied. Non-invasive microvascular
perfusion imaging with contrast-enhanced ultrasound (CEU) of the kidney and skeletal muscle under normoxic
and post-hypoxic conditions will be performed in mice pre-treated for 6 weeks with NAC, apocynin, or vehicle.
Parametric perfusion analysis (microvascular blood volume and flux rate) and dispersion modeling will be used
to better characterize the vascular events responsible for abnormal flow in the SCD model or treatment effect.
In Aim 2, CEU molecular imaging of activated von Willebrand Factor (vWF) and platelets, and PET molecular
imaging of oxidative stress will be used to further assess the microvascular molecular events responsible for
abnormal perfusion or treatment effect from the NAC or apocynin. In both of these Aims, advanced LC-MS/MS
for unbiased metabolomics and targeted identification of oxidative modification of VWF and its main regulatory
protease (ADAMTS-13), as well as other key ROS, will be performed to evaluate drug effect. In Aim 3, CEU
perfusion imaging of limb skeletal muscle, kidney, and myocardium will be performed in a pilot clinical trial
testing the hypothesis that reducing oxidative stress with NAC improves microvascular perfusion in patients
with SCD. This trial is designed as a double cross-over with NAC or placebo for 6 weeks each. The results of
this proposal will address a critical gap in our knowledge of the pathobiology of SCD and provide insight into
new therapeutic interventions. It will also provide the PI with a rich research training program (including
multidisciplinary mentorship and advisory teams, comprehensive coursework, and career advancement
resources available at the institution) that will lay the foundation to become an independent investigator who is
able to use advanced imaging and other analytic techniques in pre-clinical and clinical studies to examine
microvascular pathophysiology in hematologic disease.

## Key facts

- **NIH application ID:** 9986864
- **Project number:** 5K08HL133493-05
- **Recipient organization:** OREGON HEALTH & SCIENCE UNIVERSITY
- **Principal Investigator:** Melinda D Wu
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $174,420
- **Award type:** 5
- **Project period:** 2016-08-16 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9986864

## Citation

> US National Institutes of Health, RePORTER application 9986864, Oxidative stress in vaso-occlusion pathophysiology of sickle cell disease (5K08HL133493-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9986864. Licensed CC0.

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