von Willebrand Factor in Sickle Cell Disease Pathophysiology

描述（由申请人提供）：镰状细胞病（SCD）是一种遗传性疾病，由突变型B珠蛋白基因遗传引起，单核苷酸突变改变了一个氨基酸密码子。 突变等位基因以两个拷贝或一个拷贝沿着另一个缺陷B珠蛋白等位基因遗传。 尽管这种变化看似简单，但SCD是一种具有巨大病理负担的全身性疾病，其中大部分是由于小血管血管病变。 在这个应用程序中，我们建立在我们实验室最近的三项相关研究基础上， a）一项研究表明SCD患者在其血浆中具有高浓度的超粘附性血管性血友病因子（VWF），其量与患者的溶血速率相关，B）另一项研究表明嗜中性粒细胞氧化剂对VWF的氧化增加了其血小板结合功能并使其对ADAMTS 13裂解具有抗性，和c）证明抗氧化剂药物N-乙酰半胱氨酸（NAC）在体外和缺乏ADAMTS 13的活小鼠中降低VWF大小和反应性的研究。 我们提出了三个特定目的，旨在1）通过将VWF的数量和功能状态与疾病活动参数相关联，进一步研究VWF在SCD中的作用; 2）在SCD小鼠模型中检查对VWF缺乏或活动过度（ADAMTS 13缺乏）的疾病表现的影响; 3）评估NAC作为SCD急性和长期治疗的潜在治疗剂的作用。 我们希望这些研究能为SCD患者带来巨大的益处，产生疾病的生物标志物，提高对其病理生理学的认识，并可能产生安全廉价的药物新疗法。 公共卫生相关性：本申请中提出的研究旨在提高我们对称为von Willebrand因子（VWF）的大的粘性血浆蛋白在镰状细胞病中的作用的理解，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程度和并发症，以及潜在的新疗法。

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.