This application from the University of North Carolina (UNC) at Chapel Hill is submitted in response to RFAHL- 13-005, entitled Excellence in Hemoglobinopathies Research Award (EHRA). We have assembled an outstanding multi-disciplinary team of basic and clinical scientists, who will focus on basic mechanistic studies that may lead to the development of new therapies for the treatment of sickle cell disease (SCD). Although SCD is a hemoglobin disorder, many groups have now demonstrated that it is associated with a complex vascular pathophysiology that results in multifocal vascular occlusion and end organ dysfunction. Our group has made the exciting, new discovery that inhibition of tissue factor, which is the primary cellular initiator of the coagulation cascade, not only reduces coagulation but also inflammation and endothelial activation in two mouse model of SCD. Our results further indicate that 'cross-talk' between coagulation and these systems is mediated by protease activated receptor-1 (PAR-1) and PAR-2. We propose the novel concept that targeted inhibition of coagulation proteases and/or PAR-2 represents a potentially viable and efficacious strategy to treat patients with SCD, for whom there are currently very few therapeutic options. In pre-clinical studies, we will evaluate the effects of agents that specifically target the extrinsic, intrinsic or final commn coagulation pathways on coagulation and inflammation, as well as endothelial activation. In a complementary proof-of-concept clinical trial with the newly available factor Xa (FXa) inhibitor rivaroxaban, we will determine whether the effect of FXa inhibition extends beyond simple anticoagulation in patients with SCD. The outstanding academic environment at UNC will be leveraged to develop a Training Research Core that will supervise the recruitment and career development of young MD and PhD investigators pursuing a research career in hemoglobinopathies

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project--Cooperative Agreements (U01)
Project #
4U01HL117659-04
Application #
9069961
Study Section
Special Emphasis Panel (ZHL1)
Program Officer
Hanspal, Manjit
Project Start
2013-08-15
Project End
2018-05-31
Budget Start
2016-06-01
Budget End
2017-05-31
Support Year
4
Fiscal Year
2016
Total Cost
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
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