The PI of this application is a physician-scientist with a career focus on developing improved care for patients with sickle cell disease (SCD). The acute chest syndrome (ACS) represents a serious, potentially fatal inflammatory lung injury syndrome occurring in patients with SCD. ACS shares many features of the inflammatory lung injury associated with acute lung injury and is the second most common cause of SCD hospitalization;is a major cause of acute and chronic SCD morbidity and mortality, is the leading cause of SCD ICU admission and premature death. There is increasing appreciation that ACS is an acute hypoxia-induced lung injury syndrome targeting the lung endothelium in response to multiple exogenous insults or triggers leading to pulmonary erythrocyte sequestration, an exaggerated inflammatory response, increased expression of adhesion molecules and impairment of pulmonary vascular function. In this highly translational proposal we will address the hypothesis that vascular-targeted genetic and genomic strategies for ACS will lead to better understanding of the pathobiology of ACS, generate novel ACS biomarkers in SCD patients and produce vascular-specific therapies for ameliorating this devastating health disparity. To address this hypothesis, in Specific Aim #1 we will identify novel single nucleotide polymorphisms that modulate ACS susceptibility and generate an ACS risk- conferring SNP panel.
Specific Aim #2 will refine and validate genome-wide, vascular-centric genomic of ACS risk in SCD patients.
In Specific Aim #3 we will interrogate the involvement of vascular permeability-regulatory pathway genes and proteins in murine ACS and ALI. Together, these highly translational approaches hold the promise to identify novel targets and biomarkers that may lead to better treatment options for patients with ACS.
This project will investigate the role of new genetic markers as risk factors for the development of acute chest syndrome, a major cause of death in patients with sickle cell disease. We will also investigate the role of genetic markers as a tool to identif patients with acute chest syndrome.
|Singla, Sunit; Chen, Jiwang; Sethuraman, Shruthi et al. (2017) Loss of lung WWOX expression causes neutrophilic inflammation. Am J Physiol Lung Cell Mol Physiol 312:L903-L911|
|Ebenezer, David L; Fu, Panfeng; Suryadevara, Vidyani et al. (2017) Epigenetic regulation of pro-inflammatory cytokine secretion by sphingosine 1-phosphate (S1P) in acute lung injury: Role of S1P lyase. Adv Biol Regul 63:156-166|
|Chen, Jiwang; Sysol, Justin R; Singla, Sunit et al. (2017) Nicotinamide Phosphoribosyltransferase Promotes Pulmonary Vascular Remodeling and Is a Therapeutic Target in Pulmonary Arterial Hypertension. Circulation 135:1532-1546|
|Desai, Ankit A; Lei, Zhengdeng; Bahroos, Neil et al. (2017) Association of circulating transcriptomic profiles with mortality in sickle cell disease. Blood 129:3009-3016|
|Sysol, Justin R; Chen, Jiwang; Singla, Sunit et al. (2017) MicroRNA-1 Is Decreased by Hypoxia and Contributes to the Development of Pulmonary Vascular Remodeling via Regulation of Sphingosine Kinase 1. Am J Physiol Lung Cell Mol Physiol :ajplung000572017|
|Oliveira, Suellen D S; Castellon, Maricela; Chen, Jiwang et al. (2017) Inflammation-induced caveolin-1 and BMPRII depletion promotes endothelial dysfunction and TGF-?-driven pulmonary vascular remodeling. Am J Physiol Lung Cell Mol Physiol 312:L760-L771|
|Singla, Sunit; Sysol, Justin R; Dille, Benjamin et al. (2017) Hemin Causes Lung Microvascular Endothelial Barrier Dysfunction by Necroptotic Cell Death. Am J Respir Cell Mol Biol 57:307-314|
|Saraf, Santosh L; Shah, Binal N; Zhang, Xu et al. (2017) APOL1, ?-thalassemia, and BCL11A variants as a genetic risk profile for progression of chronic kidney disease in sickle cell anemia. Haematologica 102:e1-e6|
|Saraf, Santosh L; Akingbola, Titilola S; Shah, Binal N et al. (2017) Associations of ?-thalassemia and BCL11A with stroke in Nigerian, United States, and United Kingdom sickle cell anemia cohorts. Blood Adv 1:693-698|
|Maron, Bradley A; Machado, Roberto F; Shimoda, Larissa (2016) Pulmonary vascular and ventricular dysfunction in the susceptible patient (2015 Grover Conference series). Pulm Circ 6:426-438|
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