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
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