In order to identify new biomarkers to assess the status of patients with sickle cell disease (SCD) we have assembled a team of 5 principal investigators with expertise encompassing clinical investigation, immunology, biomedical engineering and microvascular imaging. The overarching hypothesis underlying our proposal is that the severity of tissue injury in SCD is related to the state of inflammation and vascular perfusion. Our goals are to apply minimally invasive techniques for sensitively assessing inflammation and microvascular occlusion to the analysis of mouse and human SCD: 1) flow cytometry of patient blood to measure iNKT cell activation;and 2) contrast enhanced ultrasound (CEU) to measure vascular volume/perfusion in situ in mice and people. These are validated safe techniques borrowed from the fields of immunology and cardiology. We will relate these measures to other disease indices such as clinical status in people and pulmonary function and intravital microscopy in mice. We recently discovered that iNKT cells, which can be inhibited by activation of adenosine A2A receptors (A2ARs), are activated in mice or persons with SCD. We initiated an ongoing clinical investigation (NIH RC2HL101367) facilitated by the availability of the drug regadenoson, an FDA approved A2AR agonist. Another ongoing SCD clinical trial is evaluating GMI-1070, a pan-selectin inhibitor, to reduce leukocyte adhesion to endothelial cells (EC) and vaso-occlusive episodes. To study leukocyte-EC interactions in greater depth we recruited an authority on adhesion molecules and intravital microscopy. In order to study microvascular perfusion in mice and people we recruited an expert in the technique of CEU to measure vascular perfusion in mouse and human studies. Millions of patients have undergone CEU to measure vascular perfusion in heart and other tissues. These methods will be used to assess three SCD drug candidates in mice and when possible, human studies. These are regadenoson;GMI- 1070;and ATL-801, a preclinical A2BR antagonist that inhibits RBC sickling. After they are validated, our goal is to transfer these techniques to SCD clinical trial sites. We hypothesize that the identification of new biomarkers, flow cytometric and CEU, will be more useful indices of drug effectiveness than currently used clinical outcome measures. In addition, these studies will provide new information about the cellular and molecular events that trigger vaso-occlusion and tissue ischemia in SCD.

Public Health Relevance

This project will use ultrasound to measure tissue vascular perfusion, and will analyze white blood cells from patients with sickle cell anemia. These procedures will provide us with measures of abnormalities in blood flow and inflammation that will be used to better understand the disease, and also to help evaluate the effectiveness of new therapeutic approaches.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL111969-01
Application #
8222685
Study Section
Hypertension and Microcirculation Study Section (HM)
Program Officer
Kindzelski, Andrei L
Project Start
2012-01-01
Project End
2016-12-31
Budget Start
2012-01-01
Budget End
2012-12-31
Support Year
1
Fiscal Year
2012
Total Cost
$904,227
Indirect Cost
$254,714
Name
La Jolla Institute
Department
Type
DUNS #
603880287
City
La Jolla
State
CA
Country
United States
Zip Code
92037
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Davidson, Brian P; Belcik, J Todd; Mott, Brian H et al. (2016) Quantification of residual limb skeletal muscle perfusion with contrast-enhanced ultrasound during application of a focal junctional tourniquet. J Vasc Surg 63:148-53
Kuwano, Yoshihiro; Adler, Micha; Zhang, Hong et al. (2016) G?i2 and G?i3 Differentially Regulate Arrest from Flow and Chemotaxis in Mouse Neutrophils. J Immunol 196:3828-33
Shim, Chi Young; Liu, Ya Ni; Atkinson, Tamara et al. (2015) Molecular Imaging of Platelet-Endothelial Interactions and Endothelial von Willebrand Factor in Early and Mid-Stage Atherosclerosis. Circ Cardiovasc Imaging 8:e002765

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