Cerebrovascular disease is one of the leading causes of death in the USA, with more than 140,000 people dying each year from a stroke. While age remains the greatest risk factor for stroke, other conditions are also known to predispose individuals, including hypertension, obesity, and diabetes. Other comorbid conditions, such as coagulopathies, congenital heart disease and sickle cell disease (SCD), render both adults and children vulnerable to ischemic stroke. For example, about 24% of SCD patients have a stroke by the age of 45 and 11% by the age of 20. Based on our preliminary findings and evidence already in the literature, this project will use pharmacological and genetic approaches to address the important role that neutrophils play in blood flow impairment in the cerebral microvasculature that is associated with SCD. Overall the results obtained will lead to further understanding the prothrombogenic phenotype of SCD and the potential implication of targeting neutrophils as a therapeutic strategy and treatment for this debilitating and life threatening disease.

Public Health Relevance

Sickle cell disease (SCD) is a chronic, genetic disease that affects millions of people worldwide, particularly those with African, Spanish, Mediterranean, and Indian ancestry. Many morbid consequences of SCD, such as stroke, are believed to result from problems associated with the blood flow. For example, about 24% of SCD patients have a stroke by the age of 45 and 11% by the age of 20. Based on our preliminary findings and evidence already in the literature, this project will address the important role that neutrophils play in blood flow impairment in the cerebral microvasculature, which is associated with SCD. Overall the results obtained will lead to further understanding the prothrombogenic phenotype of SCD and the potential implication of targeting neutrophils as a therapeutic strategy and treatment for this debilitating and life threatening disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
High Priority, Short Term Project Award (R56)
Project #
1R56HL125572-01A1
Application #
9130422
Study Section
Brain Injury and Neurovascular Pathologies Study Section (BINP)
Program Officer
Lerner, Norma B
Project Start
2015-09-11
Project End
2016-08-31
Budget Start
2015-09-11
Budget End
2016-08-31
Support Year
1
Fiscal Year
2015
Total Cost
$362,500
Indirect Cost
$112,500
Name
Louisiana State University Hsc Shreveport
Department
Physiology
Type
Schools of Medicine
DUNS #
095439774
City
Shreveport
State
LA
Country
United States
Zip Code
71103
Gillespie, Scarlett; Holloway, Paul M; Becker, Felix et al. (2018) The isothiocyanate sulforaphane modulates platelet function and protects against cerebral thrombotic dysfunction. Br J Pharmacol :
Smith, Helen K; Omura, Seiichi; Vital, Shantel A et al. (2018) Metallothionein I as a direct link between therapeutic hematopoietic stem/progenitor cells and cerebral protection in stroke. FASEB J 32:2381-2394
Ansari, Junaid; Moufarrej, Youmna E; Pawlinski, Rafal et al. (2018) Sickle cell disease: a malady beyond a hemoglobin defect in cerebrovascular disease. Expert Rev Hematol 11:45-55
Vital, Shantel A; Becker, Felix; Holloway, Paul M et al. (2016) Formyl-Peptide Receptor 2/3/Lipoxin A4 Receptor Regulates Neutrophil-Platelet Aggregation and Attenuates Cerebral Inflammation: Impact for Therapy in Cardiovascular Disease. Circulation 133:2169-79
Holloway, Paul M; Gavins, Felicity N E (2016) Modeling Ischemic Stroke In Vitro: Status Quo and Future Perspectives. Stroke 47:561-9
Holloway, Paul M; Gillespie, Scarlett; Becker, Felix et al. (2016) Sulforaphane induces neurovascular protection against a systemic inflammatory challenge via both Nrf2-dependent and independent pathways. Vascul Pharmacol 85:29-38