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.
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.
|Moccetti, Federico; Weinkauf, Craig C; Davidson, Brian P et al. (2018) Ultrasound Molecular Imaging of Atherosclerosis Using Small-Peptide Targeting Ligands Against Endothelial Markers of Inflammation and Oxidative Stress. Ultrasound Med Biol 44:1155-1163|
|Yu, Jennifer C; Lin, Gene; Field, Joshua J et al. (2018) Induction of antiinflammatory purinergic signaling in activated human iNKT cells. JCI Insight 3:|
|Lindner, Jonathan R; Link, Jeanne (2018) Molecular Imaging in Drug Discovery and Development. Circ Cardiovasc Imaging 11:e005355|
|Davidson, Brian P; Belcik, J Todd; Landry, Gregory et al. (2017) Exercise versus vasodilator stress limb perfusion imaging for the assessment of peripheral artery disease. Echocardiography 34:1187-1194|
|Belcik, J Todd; Davidson, Brian P; Xie, Aris et al. (2017) Augmentation of Muscle Blood Flow by Ultrasound Cavitation Is Mediated by ATP and Purinergic Signaling. Circulation 135:1240-1252|
|Wu, Melinda D; Atkinson, Tamara M; Lindner, Jonathan R (2017) Platelets and von Willebrand factor in atherogenesis. Blood 129:1415-1419|
|Chadderdon, S M; Belcik, J T; Bader, L et al. (2016) Vasoconstrictor eicosanoids and impaired microvascular function in inactive and insulin-resistant primates. Int J Obes (Lond) 40:1600-1603|
|Lindner, Jonathan R (2016) Phase-Conversion Nanoparticle Contrast Agents: Do Good Things Come in Small Packages? Circ Cardiovasc Imaging 9:|
|Chadderdon, Scott M; Belcik, J Todd; Bader, Lindsay et al. (2016) Temporal Changes in Skeletal Muscle Capillary Responses and Endothelial-Derived Vasodilators in Obesity-Related Insulin Resistance. Diabetes 65:2249-57|
|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|
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