Vasculopathy associated with Sickle Cell Disease (SCD) is multifactorial and the pathogenesis remains incompletely understood. To date, both clinical and experimental evidence concludes that reduced NO bioavailability and/or responsiveness is a contributing factor to vasculopathy in SCD. This proposal aims to elucidate a novel reduction-oxidation (redox) regulation mechanism ? the CyB5R3-depenent reduction of sGC- that controls NO sensitivity in vascular smooth muscle cells (VSMCs) and its impact on vasculopathy and in SCD. Importantly, by using a bench-to-bedside approach, we characterize this signaling pathway with gain and loss of function in cell culture. We explore the impact of this signaling pathway on the development of vasculopathy in the humanized transgenic sickle cell mouse (BERK) and chimeras transplanted into a tamoxifen-inducible Cre-Lox smooth muscle specific CyB5R3 knock-out. Finally we will extend these insights to the bedside by characterizing the effect of loss of function CyB5R3 T117S polymorphic variants on endothelial function. We test a personalized or precision medicine approach to improve the health of individuals with SCD with PH, via the targeting of new sGC modulator drugs to responsive Cyb5R3 genotypes. Considering the defining role of sGC in NO signaling and the fact that the oxidation state of sGC may predict responses to new classes of sGC activator and stimulator medications, we anticipate that these studies will significantly impact our understanding of biology, precision therapeutics (right drug for the right patient) and pharmacogenetics (polymorphism based drug selection).

Public Health Relevance

As Sickle Cell Disease (SCD) patients age, many develop progressive vasculopathy characterized by systemic and pulmonary hypertension, endothelial dysfunction, and intimal and smooth muscle proliferative changes in blood vessels. This proposal seeks to advance biology and medicine by elucidating a novel reduction-oxidation (redox) regulation mechanism ? the CyB5R3-depenent reduction of sGC- that controls NO sensitivity in vascular smooth muscle cells and its impact on vasculopathy in SCD in animals and humans.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL133864-04
Application #
9749982
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Qasba, Pankaj
Project Start
2016-09-01
Project End
2020-07-31
Budget Start
2019-08-01
Budget End
2020-07-31
Support Year
4
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Pittsburgh
Department
Pharmacology
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Durgin, Brittany G; Straub, Adam C (2018) Redox control of vascular smooth muscle cell function and plasticity. Lab Invest 98:1254-1262
Schmidt, Heidi M; Kelley, Eric E; Straub, Adam C (2018) The impact of xanthine oxidase (XO) on hemolytic diseases. Redox Biol 21:101072
Potoka, Karin P; Wood, Katherine C; Baust, Jeffrey J et al. (2018) Nitric Oxide-Independent Soluble Guanylate Cyclase Activation Improves Vascular Function and Cardiac Remodeling in Sickle Cell Disease. Am J Respir Cell Mol Biol 58:636-647
Shah, Rohan C; Sanker, Subramaniam; Wood, Katherine C et al. (2018) Redox regulation of soluble guanylyl cyclase. Nitric Oxide 76:97-104
Yu, Francois T H; Chen, Xucai; Straub, Adam C et al. (2017) The Role of Nitric Oxide during Sonoreperfusion of Microvascular Obstruction. Theranostics 7:3527-3538
Jacob, Seethal A; Novelli, Enrico M; Isenberg, Jeffrey S et al. (2017) Thrombospondin-1 gene polymorphism is associated with estimated pulmonary artery pressure in patients with sickle cell anemia. Am J Hematol 92:E31-E34
Triantafyllou, Georgios A; Straub, Adam C (2017) Letter by Triantafyllou and Straub Regarding Article, ""Thresholds for Ambulatory Blood Pressure Among African Americans in the Jackson Heart Study"". Circulation 136:2395-2396
Galley, Joseph C; Straub, Adam C (2017) Redox Control of Vascular Function. Arterioscler Thromb Vasc Biol 37:e178-e184
Alvarez, Roger A; Miller, Megan P; Hahn, Scott A et al. (2017) Targeting Pulmonary Endothelial Hemoglobin ? Improves Nitric Oxide Signaling and Reverses Pulmonary Artery Endothelial Dysfunction. Am J Respir Cell Mol Biol 57:733-744
Rahaman, Mizanur M; Nguyen, Anh T; Miller, Megan P et al. (2017) Cytochrome b5 Reductase 3 Modulates Soluble Guanylate Cyclase Redox State and cGMP Signaling. Circ Res 121:137-148

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