Abstract

Pulmonary arterial hypertension (PAH), a rare, debilitating and fatal disease for which there is currently no available cure. There is compelling evidence that the Sphingosine kinase1/S1P signaling axis is a novel and therapeutic target for PAH. To facilitate the translation of current in vivo and in vitro observations on the role of S1P dependent signaling in PAH pathobiology, this proposal will explore the hypothesis that the Sphingosine kinase1/S1P signaling axis regulates physiologic, cellular and molecular pathways in PAH that result in pulmonary vascular remodeling. SA1 seeks to define the role of LncRNA Khps1 in miR-1 and SPHK1 expression and promoting pulmonary vascular remodeling. SA2 seeks to define molecular mechanisms by which LncRNA Khps1/SPHK1 regulate pulmonary artery smooth muscle cell mitochondrial dynamics. SA3 will investigate the role of SPHK1 in aberrant chromatin remodeling and gene expression in the development of pulmonary vascular remodeling.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL127342-05
Application #
10072350
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Fessel, Joshua P
Project Start
2016-01-05
Project End
2024-06-30
Budget Start
2020-08-01
Budget End
2021-06-30
Support Year
5
Fiscal Year
2020
Total Cost
Indirect Cost

  Institution

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

  Publications

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
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
DeLalio, Leon J; Keller, Alexander S; Chen, Jiwang et al. (2018) Interaction Between Pannexin 1 and Caveolin-1 in Smooth Muscle Can Regulate Blood Pressure. Arterioscler Thromb Vasc Biol 38:2065-2078
Dai, Zhiyu; Zhu, Maggie M; Peng, Yi et al. (2018) Therapeutic Targeting of Vascular Remodeling and Right Heart Failure in Pulmonary Arterial Hypertension with a HIF-2? Inhibitor. Am J Respir Crit Care Med 198:1423-1434
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
Marsboom, Glenn; Chen, Zhenlong; Yuan, Yang et al. (2017) Aberrant Caveolin-1-Mediated Smad Signaling and Proliferation Identified by Analysis of Adenine 474 Deletion Mutation (c.474delA) in Patient Fibroblasts: A New Perspective in the Mechanism of Pulmonary Hypertension. Mol Biol Cell :
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

Showing the most recent 10 out of 23 publications