Sickle cell disease (SCD) is a genetic disease caused by inheritance of a mutant b globin gene with a single nucleotide mutation that changes one amino acid codon. The mutant alleles are inherited either as two copies, or as one copy along with another defective b globin allele. In spite of this seemingly simple change, SCD is a systemic disease with an enormous burden of pathology, much of it due to a small vessel vasculopathy. In this application, we build on three relevant recent studies from our laboratory, a) one demonstrating that SCD patients have high concentrations of hyperadhesive von Willebrand factor (VWF) in their plasma, the quantity of which correlates with the rate of hemolysis in the patients, b) another study showing that VWF oxidation by neutrophil oxidants increases its platelet binding functions and renders it resistant to ADAMTS13 cleavage, and c) a study demonstrating that N-acetylcysteine (NAC), an antioxidant drug, decreases VWF size and reactivity both in vitro and in live mice deficient in ADAMTS13. We propose three Specific Aims designed to 1) further investigate the role of VWF in SCD by correlating the quantity and functional state of VWF with parameters of disease activity;2) examine in a mouse model of SCD the effect on disease manifestations of VWF deficiency or hyperactivity (ADAMTS13 deficiency);and 3) evaluate the effect of NAC as a potential therapeutic for both acute and long-term treatment of SCD. We expect these studies to yield huge benefits for patients suffering from SCD, generating biomarkers of disease, improved knowledge of its pathophysiology, and potentially producing new therapy with a drug that is safe and inexpensive.
The studies proposed in this application are designed to improve our understanding of the role in sickle cell disease of a large, sticky plasma protein called von Willebrand factor (VWF) and to examine the potential of a widely used and safe drug, N-acetylcysteine, to treat the disease. The work will generate information that will allow us to predict disease severity and complications as well as a potential new therapy for the disease.
|Chen, Junmei; Chung, Dominic W (2018) Inflammation, von Willebrand factor, and ADAMTS13. Blood 132:141-147|
|Gust, Juliane; Hay, Kevin A; Hanafi, Laïla-Aïcha et al. (2017) Endothelial Activation and Blood-Brain Barrier Disruption in Neurotoxicity after Adoptive Immunotherapy with CD19 CAR-T Cells. Cancer Discov 7:1404-1419|
|Interlandi, Gianluca; Yakovenko, Olga; Tu, An-Yue et al. (2017) Specific electrostatic interactions between charged amino acid residues regulate binding of von Willebrand factor to blood platelets. J Biol Chem 292:18608-18617|
|Grant, Marianne A; Beeler, David L; Spokes, Katherine C et al. (2017) Identification of extant vertebrate Myxine glutinosa VWF: evolutionary conservation of primary hemostasis. Blood 130:2548-2558|
|Chung, Dominic W; Chen, Junmei; Ling, Minhua et al. (2016) High-density lipoprotein modulates thrombosis by preventing von Willebrand factor self-association and subsequent platelet adhesion. Blood 127:637-45|
|Graham, Susan M; Chen, Junmei; Chung, Dominic W et al. (2016) Endothelial activation, haemostasis and thrombosis biomarkers in Ugandan children with severe malaria participating in a clinical trial. Malar J 15:56|
|Zheng, Ying; Chen, Junmei; López, José A (2015) Flow-driven assembly of VWF fibres and webs in in vitro microvessels. Nat Commun 6:7858|
|Wang, Yi; Chen, Junmei; Ling, Minhua et al. (2015) Hypochlorous acid generated by neutrophils inactivates ADAMTS13: an oxidative mechanism for regulating ADAMTS13 proteolytic activity during inflammation. J Biol Chem 290:1422-31|
|Chen, Junmei; Hinckley, Jesse D; Haberichter, Sandra et al. (2015) Variable content of von Willebrand factor mutant monomer drives the phenotypic variability in a family with von Willebrand disease. Blood 126:262-9|