Midwest Sickle Cell Center (MSCC)

描述(由申请人提供)：中西部镰状细胞中心(MSCC)建立在威斯康星医学院和华盛顿大学医学院多学科研究镰状细胞病(SCD)团队之间长期存在的科学关系的基础上。MSCC将基础研究、转化研究、临床结果分析和卓越的综合临床服务结合在一起，以提高对SCD并发症的理解和管理。中心间项目1将在一项双盲、随机、安慰剂对照试验中测试在急性血管闭塞事件的标准治疗中加入静脉镁的安全性和有效性。虽然主要结果是安全性和住院时间，但该项目还将调查镁疗法对一氧化氮途径和内皮功能障碍的影响，与项目4和项目5协同。患者结果项目3将开发一个儿科和SCD特定的健康相关生活质量模块，这将是从患者的角度衡量SCD影响和治疗效果的关键工具。基础项目4将通过检测一氧化氮、脂质氧化和游离血红蛋白之间的相互作用，研究溶血在人类和小鼠SCD中发现的血管反应改变中的作用。翻译项目5将研究半胱氨酰白三烯和慢性炎症在SCD病理发展中的作用。基础科学部分将使用半胱氨酰白三烯受体抑制剂孟鲁司特探索人类和小鼠SCD的生物学机制。项目5的临床部分将进行安全性试验，以确保孟鲁司特不会增加发病率(疼痛)，并进行可行性试验，以确定孟鲁司特是否有可能减少炎症反应的系统性措施。行政核心A将为MSCC提供科学、财政和行政支持。除了为患有SCD的儿童和成人提供严格的最先进的全面护理外，临床核心B还将作为所有三个中心内项目和计划中的合作中心间试验中的人类受试者研究的临床研究基础设施。患者服务核心C将专注于为受SCD影响的患者、家庭和社区提供教育服务。最后，动物核心D将为项目4和5中使用小鼠模型的活体研究提供必要的服务和专业知识。

DESCRIPTION (provided by applicant): The Midwest Sickle Cell Center (MSCC) is built upon the longstanding scientific relationship that exists between the multi-disciplinary research sickle cell disease (SCD) teams at the Medical College of Wisconsin and Washington University School of Medicine. The MSCC unites basic research, translational research, clinical outcomes analyses, and excellent comprehensive clinical services to improve the understanding and management of complications of SCD. Inter-Center Project 1 will test the safety and efficacy of the addition of intravenous magnesium to standard therapy for acute vaso-occlusive events in a double-blind, randomized, placebo-controlled trial. While the primary outcomes are safety and length of hospital stay, this Project will also investigate the effect of magnesium therapy on the nitric oxide pathway and endothelial dysfunction, synergizing with Projects 4 and 5. Patient Outcomes Project 3 will develop a pediatric- and SCD-specific health-related quality of life module that will be a critical tool to measure the impact of SCD and effect of treatment from the perspective of the patient. Basic Project 4 will study the role of hemolysis in the altered vascular responses found in human and murine SCD by examining the interplay between nitric oxide, lipid oxidation and cell free hemoglobin. Translational Project 5 will examine the role of cysteinyl leukotrienes and chronic inflammation in the development of SCD pathologies. The basic science component will explore biological mechanisms in both human and murine SCD using the cysteinyl leukotriene receptor inhibitor, montelukast. The clinical portion of Project 5 will conduct a safety trial to assure that montelukast does not increase morbidity (pain) and a feasibility trial to determine if montelukast has the potential to reduce the systemic measures of the inflammatory response. Administrative Core A will provide scientific, fiscal and administrative support for the MSCC. In additional to providing rigorous sate-of-the-art comprehensive care for children and adults with SCD, Clinical Core B will serve as the clinical research infrastructure for human subjects research within all three intra-Center Projects and the planned collaborative inter-Center trials. Patient Services Core C will focus on educational services for patients, families and communities impacted by SCD. Finally, Animal Core D will provide essential services and expertise for the in vivo studies using murine models in Projects 4 and 5.