von Willebrand Factor in Sickle Cell Disease Pathophysiology

镰状细胞病病理生理学中的冯维勒布兰德因子

• 批准号: 8427280
• 负责人: Barbara A Konkle
• 金额: $ 71.04万
• 依托单位: BLOODWORKS
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-02-15 至 2017-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8427280
• 关键词: Acetylcysteine; Acute; Address; Adhesiveness; Adult; Alleles; Amino Acids; Antioxidants; Binding; Biological Markers; Blood Platelets; Bone Marrow; Clinical; Codon Nucleotides; Congenic Mice; Data; Disease; Dose; Endothelium; Erythrocytes; Functional disorder; Genes; Globin; Goals; Hemolysis; Hereditary Disease; Human; Hyperactive behavior; In Vitro; Inherited; Knowledge; Laboratories; Life; Mus; Mutation; Nucleotides; Oxidants; Oxidative Stress; Pain; Pathology; Patients; Pharmaceutical Preparations; Plasma; Plasma Proteins; Resistance; Role; Safety; Severities; Severity of illness; Sickle Cell; Sickle Cell Anemia; Systemic disease; Therapeutic; Transplantation; Vascular Diseases; Work; base; cohort; design; improved; indexing; intravital microscopy; mouse model; mutant; neutrophil; oxidation; prevent; research study; von Willebrand Disease; von Willebrand Factor

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.

描述（申请人提供）：镰状细胞病（SCD）是一种遗传性疾病，由突变b珠蛋白基因遗传引起，该基因具有改变一个氨基酸密码子的单核苷酸突变。 突变等位基因要么作为两个拷贝遗传，要么作为一个拷贝与另一个有缺陷的b球蛋白等位基因一起遗传。 尽管这种变化看似简单，但 SCD 是一种全身性疾病，具有巨大的病理负担，其中大部分是由于小血管病变所致。 在此应用程序中，我们以我们实验室最近的三项相关研究为基础， a) 一项研究表明，SCD 患者血浆中存在高浓度的高浓度血管性血友病因子 (VWF)，其数量与患者溶血率相关，b) 另一项研究表明，中性粒细胞氧化剂氧化 VWF 会增加其血小板结合功能并使其能够抵抗 ADAMTS13 裂解，c) 一项研究表明，N-乙酰半胱氨酸 (NAC)（一种抗氧化药物）可降低 VWF 大小和反应性在体外和缺乏 ADAMTS13 的活体小鼠中。 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，进一步研究 VWF 在 SCD 中的作用； 2) 在 SCD 小鼠模型中检查 VWF 缺乏或过度活跃（ADAMTS13 缺乏）对疾病表现的影响； 3) 评估 NAC 作为 SCD 急性和长期治疗的潜在疗法的效果。 我们预计这些研究将为 SCD 患者带来巨大益处，产生疾病的生物标志物，提高对其病理生理学的了解，并有可能产生安全且廉价的新药物疗法。