The PI of this application is a physician-scientists 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 and validate potentially functional novel single nucleotide polymorphisms (SNPs) and epigenetic modifiers that modulate ACS susceptibility.
Specific Aim #2 will interrogate necroptosis as a molecular and therapeutic target in murine ACS.
In Specific Aim #3 discover and validate biochemical and genetic necroptosis-centric biomarkers of ACS risk and a genomic signature for mortality in SCD patients. 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.

Public Health Relevance

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 identify patients with acute chest syndrome.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL111656-08
Application #
9925265
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Qasba, Pankaj
Project Start
2013-02-05
Project End
2022-04-30
Budget Start
2020-05-01
Budget End
2021-04-30
Support Year
8
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Indiana University-Purdue University at Indianapolis
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
603007902
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
Sysol, Justin R; Chen, Jiwang; Singla, Sunit et al. (2018) Micro-RNA-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 314:L461-L472
Usmani, Ashar; Machado, Roberto F (2018) Vascular complications of sickle cell disease. Clin Hemorheol Microcirc 68:205-221
Machogu, Evans M; Machado, Roberto F (2018) How I treat hypoxia in adults with hemoglobinopathies and hemolytic disorders. Blood 132:1770-1780
Saraf, Santosh L; Viner, Maya; Rischall, Ariel et al. (2018) HMOX1 and acute kidney injury in sickle cell anemia. Blood 132:1621-1625
Brittain, Evan L; Thennapan, Thennapan; Maron, Bradley A et al. (2018) Update in Pulmonary Vascular Disease 2016 and 2017. Am J Respir Crit Care Med 198:13-23
Raslan, Rasha; Shah, Binal N; Zhang, Xu et al. (2018) Hemolysis and hemolysis-related complications in females vs. males with sickle cell disease. Am J Hematol 93:E376-E380
Duarte, Julio D; Kansal, Mayank; Desai, Ankit A et al. (2018) Endothelial nitric oxide synthase genotype is associated with pulmonary hypertension severity in left heart failure patients. Pulm Circ 8:2045894018773049
Singla, Sunit; Machado, Roberto F (2018) Death of the Endothelium in Sepsis: Understanding the Crime Scene. Am J Respir Cell Mol Biol 59:3-4
Saraf, Santosh L; Sysol, Justin R; Susma, Alexandru et al. (2018) Progressive glomerular and tubular damage in sickle cell trait and sickle cell anemia mouse models. Transl Res 197:1-11
Han, Jin; Zhang, Xu; Saraf, Santosh L et al. (2018) Risk factors for vitamin D deficiency in sickle cell disease. Br J Haematol 181:828-835

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