von Willebrand Factor in Sickle Cell Disease Pathophysiology

描述(申请人提供)：镰状细胞病(SCD)是一种遗传性疾病，由突变的b珠蛋白基因遗传引起，该突变具有改变一个氨基酸密码子的单核苷酸突变。突变的等位基因要么作为两个副本遗传，要么作为一个副本与另一个有缺陷的b珠蛋白等位基因一起遗传。尽管有这种看似简单的变化，但SCD是一种全身性疾病，具有巨大的病理负担，其中很大一部分是由于小血管病变。在本申请中，我们建立在实验室最近的三项相关研究的基础上， A)一项证明SCD患者血浆中存在高浓度的高黏附性血管性血友病因子(VWF)的研究，其数量与患者的溶血率相关；b)另一项研究表明，中性粒细胞氧化剂氧化VWF可增加其与血小板的结合功能，使其对ADAMTS13裂解具有抵抗力，以及c)一项研究表明，抗氧化剂N-乙酰半胱氨酸(NAC)在体外和活着的ADAMTS13缺陷小鼠中都能降低VWF的大小和反应性。我们提出了三个具体目标：1)通过将VWF的数量和功能状态与疾病活动参数相关联来进一步研究VWF在SCD中的作用；2)在SCD小鼠模型中检测VWF缺乏或多动(ADAMTS13缺乏)对疾病表现的影响；以及3)评估NAC作为SCD急性和长期治疗的潜在治疗作用。我们预计这些研究将为SCD患者带来巨大的好处，产生疾病的生物标记物，改善对其病理生理学的知识，并有可能产生一种安全且廉价的药物的新疗法。 公共卫生相关性：本申请中提出的研究旨在提高我们对一种名为von Willebrand因子(VWF)的大型粘性血浆蛋白在镰状细胞疾病中的作用的理解，并检查广泛使用的安全药物N-乙酰半胱氨酸治疗该疾病的潜力。这项工作将产生信息，使我们能够预测疾病的严重性和并发症，以及潜在的疾病新疗法。

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. PUBLIC HEALTH RELEVANCE: 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.