von Willebrand Factor in Sickle Cell Disease Pathophysiology

描述（由申请人提供）：镰状细胞病（SCD）是一种由b珠蛋白突变基因遗传引起的遗传病，该突变基因具有改变一个氨基酸密码子的单核苷酸突变。突变等位基因要么以两个拷贝的形式遗传，要么以一个拷贝的形式与另一个有缺陷的b球蛋白等位基因一起遗传。尽管这个看似简单的改变，SCD是一种全身性疾病，病理负担沉重，其中大部分是由于小血管病变。在这个应用程序中，我们基于我们实验室最近的三项相关研究，

DESCRIPTION (provided by applicant): 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.