Sickle cell disease is a progressive vasculopathy stemming from decreased red blood cell (RBC) deformability. Vascular disease is at the heart of both acute and chronic sickle disease, including pain crisis, acute chest syndrome, stroke, skin ulcers, and pulmonary hypertension. However, the mechanisms linking decreased RBC deformability to chronic vasculopathy are multifactorial and poorly characterized. Nitric oxide (NO) is the key mediator linking blood mechanics to vessel tone and vascular remodeling. As bloodflow shears the endothelium, NO is released, causing vasodilation and inhibiting platelet aggregation. NO bioavailability is diminished in SCD because decellularized hemoglobin and arginase, released during hemolysis, scavenge NO and lower endothelial NO production. Recent evidence suggests that 50% of bioavailable NO is synthesized within RBC, themselves, though a shear-activated eNOS enzyme. RBC NO is primarily converted to nitrite and nitrosylated hemoglobins when tissue oxygenation is high, but deoxygenated hemoglobin converts these species to nitric oxide under hypoxic conductions. Thus, RBC generated NO appears to be a vital mediator of oxygen supply and demand and its role in sickle cell vasculopathy is completely unexplored. Our fundamental hypothesis is that decreased red cell deformability reduces shear-mediated nitric oxide production by the red cell itself, crippling vita """"""""storage"""""""" forms of nitric oxide, causing vascular dysfunction at several levels of the vascular system. This research proposal merges novel laboratory methods in RBC nitric oxide production with clinical investigation of vascular dysfunction in patients with sickle cell disease Multimodal characterization of the different vascular beds will lead to improved phenotypic categorization and pathophysiological links to the underlying RBC biophysical/biochemical derangements. We will also explore whether RBC-generated NO has the ability to directly affect the vasculature using aortic ring preps and whether RBC-generated NO decreases platelet aggregation. Support from this grant benefits SCD patients in three ways: 1) it improves cross- specialization (i.e. hematology and cardiology), 2) it translates novel lab based methods in RBC generation of NO to patients using vascular preps and measurement of platelet aggregation, and 3) it will set the ground work for larger clinical translational studies linking RBC-generated NO and rheology with sophisticated measures of vascular function in patients with SCD. The K23 mechanism represents the natural extension my career development to date, combining my previous laboratory and patient-oriented research expertise with the specific clinical research training necessary to conduct large translational studies of novel targets in vascular dysfunction.
Sickle cell disease (SCD) is a significant cause of morbidity and mortality throughout the world and there are more than 80,000 individuals suffering from SCD in the United States, with the annual cost of care for these patients greater than 1.1 billion dollars. Decreased red blood cell (RBC) deformability and vascular disease underlie the majority of suffering in these patients and despite improvements in overall survival, treatment is limited. Linking RBC nitric oxide production in SCD with RBC deformability and vascular disease will expose new therapeutic targets in this complex disease process.
|Simmonds, Michael J; Suriany, Silvie; Ponce, Derek et al. (2018) Red blood cell mechanical sensitivity improves in patients with sickle cell disease undergoing chronic transfusion after prolonged, subhemolytic shear exposure. Transfusion 58:2788-2796|
|Detterich, Jon A (2018) Simple chronic transfusion therapy, a crucial therapeutic option for sickle cell disease, improves but does not normalize blood rheology: What should be our goals for transfusion therapy? Clin Hemorheol Microcirc 68:173-186|
|Chalacheva, Patjanaporn; Khaleel, Maha; Sunwoo, John et al. (2017) Biophysical markers of the peripheral vasoconstriction response to pain in sickle cell disease. PLoS One 12:e0178353|
|Detterich, Jon A (2017) Myocardial fibrosis: the heart of diastole? Blood 130:104-105|
|Khaleel, Maha; Puliyel, Mammen; Shah, Payal et al. (2017) Individuals with sickle cell disease have a significantly greater vasoconstriction response to thermal pain than controls and have significant vasoconstriction in response to anticipation of pain. Am J Hematol 92:1137-1145|
|Bush, Adam; Borzage, Matthew; Detterich, John et al. (2017) Empirical model of human blood transverse relaxation at 3?T improves MRI T2 oximetry. Magn Reson Med 77:2364-2371|
|Cheng, Andrew L; Takao, Cheryl M; Wenby, Rosalinda B et al. (2016) Elevated Low-Shear Blood Viscosity is Associated with Decreased Pulmonary Blood Flow in Children with Univentricular Heart Defects. Pediatr Cardiol 37:789-801|
|Connes, Philippe; Alexy, Tamas; Detterich, Jon et al. (2016) The role of blood rheology in sickle cell disease. Blood Rev 30:111-8|
|Meloni, Antonella; Detterich, Jon; Pepe, Alessia et al. (2015) Pulmonary hypertension in well-transfused thalassemia major patients. Blood Cells Mol Dis 54:189-94|
|Chalacheva, Patjanaporn; Kato, Roberta M; Sangkatumvong, Suvimol et al. (2015) Autonomic responses to cold face stimulation in sickle cell disease: a time-varying model analysis. Physiol Rep 3:|
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