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Development of Novel Tools to Treat Vaso-Occlusive Pain in Sickle Cell Disease
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18-036S-6.2
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Development of Novel Tools to Treat Vaso-Occlusive Pain in Sickle Cell Disease
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Dr. Biree Andemariam
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This study is a prospective, clinical/translational research study with both long term and immediate goals. The long-term goals of this project are two-fold: (i) to quantitatively understand how the adhesive cellular interaction between blood cells and the endothelium can be modified to prevent VOE; (ii) To create simple point-of-care diagnostic tests that will indicate the risk of VOE onset. Our central hypothesis is that the onset of VOE is temporally-related to an increase in blood adhesion and viscosity that can be reversed with anti-adhesion therapy. The immediate goals of this project are to (1) measure the relationship between steady-state SS-RBC--endothelium adhesion and VOE frequency, and identify changes in SS-RBC--endothelium adhesion during VOE onset, (2) demonstrate an ex vivo effect of anti-adhesive therapy on SS-RBC--endothelium adhesion that directly or indirectly targets the cAMP-PKA pathway, and (3) develop simple a single-use microfluidics device capable of indicating the risk for VOE. Atomic force microscope (AFM) and microfluidics will be used to measure adhesion of endothelial proteins to human SS-RBCs isolated from SCD patients at steady-state (no VOE) and at VOE onset. AFM allows specific quantification at the single molecule level of both the number and strength of protein-protein binding events on the RBC surface. Microfluidics allow for high throughput screening. To achieve our goals, we will complete the following specific aims: Aim 1: Determine the relationship between (1) steady-state SS-RBC adhesion and frequency of VOEs and (2) changes in SS-RBC adhesion level and onset of VOEs. Aim 2: Measure the ex vivo effect of pharmacologic blockade of receptor--ligand adhesion in the B-adrenergic system. Aim 3: Design, fabricate, and validate a simple, inexpensive, single-use microfluidics device coupled with a smart-phone kit and software application that will indicate the risk for VOE onset. Our expected outcomes and accomplishments are to (1) identify a relationship between enhanced SS-RBC adhesion and VOE onset, (2) identify therapies capable of limiting the onset and duration of VOEs and (3) create a single-use microfluidics device capable of indicating the risk of VOE onset. This has the potential to impact the development of needed treatments to prevent and reverse VOEs in millions of individuals with SCD worldwide. We will enroll 5 eligible subjects with SCD and 5 healthy controls over a three-year period. During this time, each SCD subject will donate 5 baseline blood samples to ensure we establish a true baseline. Baseline blood samples will be collected periodically during routine clinic visits over the three year study enrollment; at this time, subjects will donate 12 cc of blood. SCD subjects will also document when a painful vaso-occlusive episode (VOE) occurs and will donate a total of 3-4 VOE blood samples over the three year study period. During each VOE blood draw, SCD subjects will donate 12cc of blood. The initial VOE blood sample must be obtained within 48 hours of the VOE onset. Subsequent samples can be obtained in the days following VOE onset or at the time of a new VOE episode. Healthy controls will donate 12 cc of blood on three occasions, with each blood draw being at least one month apart. Blood will be analyzed for CBC/differential, hemoglobin electrophoresis, epinephrine levels, RBC adhesion, and blood viscosity. With this approach, we will test the hypothesis that there is a relationship between steady-state SS-RBC adhesion and frequency of VOEs (Specific Aim #1). SS-RBC adhesion at VOE onset will be compared to steady-state in order to test the hypothesis that enhanced SS-RBC adhesion mediates VOE (Specific Aim #1). Utilizing blood collected from subjects with SCD during steady-state and within 48 hours of VOE onset, we will measure the adhesion of SS-RBCs to the endothelial ligands.
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Blood - Sickle Cell Disease
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Pain
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Check with study contact
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Sasia-Marie Jones. Telephone: Not available. Email: sajones@uchc.edu or Ektor Rafti. Telephone: 860-679-7021. Email: ERafti@uchc.edu
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Enrolling/recruiting. For current recruitment status, please check with study contact.
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