Sickle cell disease is caused by a nnutant form of hemoglobin that polymerizes when exposed to low oxygen tension. Polymerization makes the red blood cells rigid so that they cannot traverse some blood vessels leading to blockage of these vessels which then leads to significant morbidity and mortality. Although polymerization can be thought of as the primary cause of the disease, clinical presentation includes symptoms that result from a host of pathological states including acute and chronic inflammation, stasis, reperfusion injury, endothelial activation and dysfunction, coagulation activation, and excess oxidant stress. The link between polymerization and these pathologies is not clear. However, part ofthe link may be tied to the function of Nitric Oxide (NO), an important signaling molecule. NO is synthesized in endothelial cells of blood vessels and diffuses to neighboring smooth muscle cells where it acts as a signaling molecule, causing muscle relaxation and vasodilation. It also decreases endothelial and platelet activation, acts as an anti-oxidant, and is anti-inflammatory. Sickle red blood cells are fragile, rupturing during transit in the circulation (hemolysis). Several groups have hypothesized that cell-free hemoglobin that is released upon hemolysis efficiently scavenges NO, leading to an NO-related deficiency associated with sickle cell disease. The roles of hemolysis and NO in sickle cell disease remain controversial. This project aims to explore those roles while examining the links between polymerization, hemolysis, and other pathological consequences in sickle cell disease. This project will also examine aspects of therapeutic interventions that involve increasing nitric oxide bioavailability via nitrite therapy. The laboratories participating in this project have recently shown that, contrary to the existing paradigm, nitrite acts as a vasodilator in human circulation that is preferentially released under low oxygen conditions. Results from this project will elucidate mechanistic pathways in the pathology of sickle cell disease and nitric oxide biology and extend these insights to translational studies. As NO is important in many diseases, information gained herein will have wide application.

Public Health Relevance

This proposal aims to further explore the pathology of sickle cell disease by examining the link between the primary cause ofthe disease and clinical outcomes, largely through interactions with the important signaling molecule Nitric Oxide. The work also explores basic mechanisms that will help guide translation to therapeutic strategies aimed at restoring Nitric Oxide bioavailability in sickle cell and other diseases.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37HL058091-17
Application #
8463230
Study Section
Special Emphasis Panel (NSS)
Program Officer
Goldsmith, Jonathan C
Project Start
1998-02-01
Project End
2017-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
17
Fiscal Year
2013
Total Cost
$355,935
Indirect Cost
$68,266
Name
Wake Forest University Health Sciences
Department
Physics
Type
Schools of Arts and Sciences
DUNS #
041418799
City
Winston-Salem
State
NC
Country
United States
Zip Code
27106
Raval, Jay S; Mazepa, Marshall A; Kim-Shapiro, Daniel B et al. (2017) Rainbow of hemolysis associated with acquired thrombotic thrombocytopenic purpura. J Clin Apher 32:274-275
Hughan, Kara S; Wendell, Stacy Gelhaus; Delmastro-Greenwood, Meghan et al. (2017) Conjugated Linoleic Acid Modulates Clinical Responses to Oral Nitrite and Nitrate. Hypertension :
Wajih, Nadeem; Basu, Swati; Jailwala, Anuj et al. (2017) Potential therapeutic action of nitrite in sickle cell disease. Redox Biol 12:1026-1039
Shaltout, Hossam A; Eggebeen, Joel; Marsh, Anthony P et al. (2017) Effects of supervised exercise and dietary nitrate in older adults with controlled hypertension and/or heart failure with preserved ejection fraction. Nitric Oxide 69:78-90
Helms, Christine C; Kapadia, Shannon; Gilmore, Anne C et al. (2017) Exposure of fibrinogen and thrombin to nitric oxide donor ProliNONOate affects fibrin clot properties. Blood Coagul Fibrinolysis 28:356-364
Lee, Janet S; Kim-Shapiro, Daniel B (2017) Stored blood: how old is too old? J Clin Invest 127:100-102
Wajih, Nadeem; Liu, Xiaohua; Shetty, Pragna et al. (2016) The role of red blood cell S-nitrosation in nitrite bioactivation and its modulation by leucine and glucose. Redox Biol 8:415-21
Eggebeen, Joel; Kim-Shapiro, Daniel B; Haykowsky, Mark et al. (2016) One Week of Daily Dosing With Beetroot Juice Improves Submaximal Endurance and Blood Pressure in Older Patients With Heart Failure and Preserved Ejection Fraction. JACC Heart Fail 4:428-37
Helms, Christine C; Liu, Xiaohua; Kim-Shapiro, Daniel B (2016) Recent insights into nitrite signaling processes in blood. Biol Chem :
Ahluwalia, Amrita; Gladwin, Mark; Coleman, Gary D et al. (2016) Dietary Nitrate and the Epidemiology of Cardiovascular Disease: Report From a National Heart, Lung, and Blood Institute Workshop. J Am Heart Assoc 5:

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