Rare Diseases Clinical Research Consortia (RDCRC) for the Rare Diseases Clinical Research Network (RDCRN) (U54 Clinical Trial Optional)

总体摘要 尿素循环障碍(UCD)包括一组罕见的先天代谢错误，历史上一直是 与一度被认为高得难以治愈的死亡率和发病率有关。罕见的疾病 尿素循环障碍(UCDC)临床研究联盟在减重甚至 扭转这一可悲的局面。美国疾病控制与预防中心的重点是8个相关的障碍，涉及一个缺陷 尿素生物合成所必需的6种酶和2种膜转运体：N-乙酰谷氨酸合成酶 缺乏症；氨基甲酰磷酸合成酶I缺乏症；鸟氨酸转氨甲酸酶缺乏症； 精氨酸琥珀酸合成酶缺乏症；精氨酸琥珀酸解酶缺乏症；精氨酸酶缺乏症(精氨酸血症)； 高鸟氨酸血症、高氨血症、高瓜氨酸尿症(HHH)综合征；和瓜氨酸血症II型。 在过去的15年里，该联盟已经发展成为一个由16个学术中心组成的国际网络(其中13个在 美国，1个在加拿大，2个在欧洲)，提供最先进的护理并进行创新的临床研究 在UCD。 在下一个赠款周期中，UCDC提出了四个具体目标： 1)通过合作的临床研究，增进我们对UCD病理生理学的理解 包括三个项目：a)对受影响的人进行纵向观察性“自然历史”研究 扩大对挖掘大量编码临床数据的关注，以发现UCD的新发病率；b)临床 了解癫痫发作活动的后果并确定潜在的神经保护治疗方法的研究 高氨危象时的处理方法；c)肝脏发育的观察性研究 UCD患者随时间推移的功能障碍和紊乱，包括定义肝纤维化的生物标志物。 2)培养下一代罕见疾病研究人员的发展 初出茅庐的干部将成为稀有基因临床研究团队科学表现的专家 精神障碍，尤其是尿失禁。 3)通过实施试验性/可行性临床研究项目，确定UCD护理的有前景的新方法 将部署最先进的方法和技术来监控和跟踪诊所和 部署实现远程观测的技术。 4)传播知识，为所有人提供随时获取信息的机会，从而改善对妇幼保健服务的照顾 努力将影响结果的个人，包括研究人员(基础和临床)、医生和 通过专业会议和列表服务器、我们的网站、播客和网络研讨会联合医疗保健专业人员。的 对该联盟的重要性还将是向患者、家属、代表 政府和普通民众。该联盟将通过UCDC的年度 时事通讯、公共网站、在会议和出版物上的演讲。

OVERALL ABSTRACT Urea Cycle Disorders (UCD) comprise a group of rare inborn errors of metabolism that historically have been associated with a rate of mortality and morbidity that once was considered intractably high. The Rare Diseases Clinical Research Consortium in Urea Cycle Disorders (UCDC) has enjoyed success in attenuating and even reversing this lamentable situation. The UCDC focuses on the 8 related disorders that involve deficiencies in one of the 6 enzymes and 2 membrane transporters essential for urea biosynthesis: N-acetylglutamate synthase deficiency; Carbamyl phosphate synthase I deficiency; Ornithine transcarbamylase deficiency; Argininosuccinate synthase deficiency; Argininosuccinatelyase deficiency; Arginase deficiency (Argininemia); Hyperornithinemia, hyperammonemia, homocitrullinuria (HHH) syndrome; and Citrullinemia type II. Over the past 15 years the Consortium has developed into an international network of 16 academic centers (13 in the U.S., 1 in Canada, and 2 in Europe) that provides state-of-the-art care and conducts innovative clinical research in UCD. In the next grant cycle the UCDC proposes four specific aims: 1) To advance our understanding of the pathophysiology of UCD through collaborative clinical research that includes three projects: a) a longitudinal observational, “natural history” study of affected individuals with an expanded focus on mining the wealth of coded clinical data to uncover new morbidities in UCD; b) a clinical study to understand the consequences of seizure activity and define potential neuroprotective treatment approaches during hyperammonemic crises; and c) an observational study of the development of liver dysfunction and disorder over time in individuals with UCD, including defining biomarkers of hepatic fibrosis. 2) To nurture the development of the next generation of rare disease researchers by training this still- nascent cadre to become expert in the performance of team science clinical investigation of rare genetic disorders, especially UCD. 3) To identify promising new approaches to UCD care by performing pilot/feasibility clinical research projects that will deploy state-of-the-art methodologies and technology to monitor and track patients in the clinic and with deployment of technologies to enable remote observation. 4) To disseminate knowledge and improve the care of UCD by providing ready access to information for all individuals whose efforts will impact outcome, including researchers (both basic and clinical), physicians, and allied healthcare professionals by professional meetings and listservs, our website, podcasts and webinars. Of importance to the Consortium also will be dissemination of information to patients, families, representatives in government and the lay public. The Consortium will execute this informational role through the UCDC’s annual newsletter, public website, presentations at conferences, and publications.