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 #
5U01HL117659-02
Application #
8722604
Study Section
Special Emphasis Panel (ZHL1-CSR-C (F1))
Program Officer
Goldsmith, Jonathan C
Project Start
2013-08-15
Project End
2018-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
2
Fiscal Year
2014
Total Cost
$1,452,109
Indirect Cost
$470,954
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
Heimlich, J Brett; Chipoka, Godwin; Kamthunzi, Portia et al. (2016) Establishing sickle cell diagnostics and characterizing a paediatric sickle cell disease cohort in Malawi. Br J Haematol 174:325-9
Chandarajoti, K; Liu, J; Pawlinski, R (2016) The design and synthesis of new synthetic low-molecular-weight heparins. J Thromb Haemost 14:1135-45
Noubouossie, Denis; Key, Nigel S; Ataga, Kenneth I (2016) Coagulation abnormalities of sickle cell disease: Relationship with clinical outcomes and the effect of disease modifying therapies. Blood Rev 30:245-56
Sparkenbaugh, Erica M; Chantrathammachart, Pichika; Chandarajoti, Kasemsiri et al. (2016) Thrombin-independent contribution of tissue factor to inflammation and cardiac hypertrophy in a mouse model of sickle cell disease. Blood 127:1371-3
Ataga, Kenneth I; Stocker, Jonathan (2015) The trials and hopes for drug development in sickle cell disease. Br J Haematol 170:768-80
Sparkenbaugh, Erica M; Chantrathammachart, Pichika; Wang, Shaobin et al. (2015) Excess of heme induces tissue factor-dependent activation of coagulation in mice. Haematologica 100:308-14
Noubouossie, Denis; Key, Nigel S (2015) Sickle cell disease and venous thromboembolism in pregnancy and the puerperium. Thromb Res 135 Suppl 1:S46-8
Folsom, A R; Tang, W; Roetker, N S et al. (2015) Prospective study of sickle cell trait and venous thromboembolism incidence. J Thromb Haemost 13:2-9
Freeman, Ashley T; Ataga, Kenneth I (2015) Pulmonary endarterectomy as treatment for chronic thromboembolic pulmonary hypertension in sickle cell disease. Am J Hematol 90:E223-4
Key, Nigel S; Connes, Philippe; Derebail, Vimal K (2015) Negative health implications of sickle cell trait in high income countries: from the football field to the laboratory. Br J Haematol 170:5-14

Showing the most recent 10 out of 27 publications