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 #
5U01HL117659-03
Application #
8857241
Study Section
Special Emphasis Panel (ZHL1)
Program Officer
Hanspal, Manjit
Project Start
2013-08-15
Project End
2016-05-31
Budget Start
2015-06-01
Budget End
2016-05-31
Support Year
3
Fiscal Year
2015
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
Thrower, Ashley; Ciccone, Emily J; Maitra, Poulami et al. (2018) Effect of renin-angiotensin-aldosterone system blocking agents on progression of glomerulopathy in sickle cell disease. Br J Haematol :
Heimlich, J Brett; Chipoka, Godwin; Elsherif, Laila et al. (2018) Nephrin as a biomarker of sickle cell glomerulopathy in Malawi. Pediatr Blood Cancer 65:e26993
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
Bello, Natalie A; Hyacinth, Hyacinth I; Roetker, Nicholas S et al. (2017) Sickle cell trait is not associated with an increased risk of heart failure or abnormalities of cardiac structure and function. Blood 129:799-801
Xu, Yongmei; Chandarajoti, Kasemsiri; Zhang, Xing et al. (2017) Synthetic oligosaccharides can replace animal-sourced low-molecular weight heparins. Sci Transl Med 9:
Noubouossie, Denis F; Whelihan, Matthew F; Yu, Yuan-Bin et al. (2017) In vitro activation of coagulation by human neutrophil DNA and histone proteins but not neutrophil extracellular traps. Blood 129:1021-1029
Hebbel, Robert P; Key, Nigel S (2016) Microparticles in sickle cell anaemia: promise and pitfalls. Br J Haematol 174:16-29
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
Whelihan, M F; Lim, M Y; Mooberry, M J et al. (2016) Thrombin generation and cell-dependent hypercoagulability in sickle cell disease. J Thromb Haemost 14:1941-1952

Showing the most recent 10 out of 35 publications