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性代谢缺陷， 与死亡率和发病率相关，这曾经被认为是难以解决的高。罕见病 尿素循环障碍临床研究联合会（UCDC）在减轻甚至减少尿素循环障碍方面取得了成功。 扭转这种可悲的局面。UCDC专注于8个相关的疾病，涉及一个缺陷 在尿素生物合成所必需的6种酶和2种膜转运蛋白中：N-乙酰谷氨酸合酶 鸟氨酸转氨甲酰酶缺乏症; 精氨酸琥珀酸合酶缺乏症;精氨酸琥珀酸裂解酶缺乏症;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（HHH）综合征;和瓜氨酸血症II型。来 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（13个在 美国，1家在加拿大，2家在欧洲），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，UCDC提出了四个具体目标： 1)通过合作临床研究，促进我们对UCD病理生理学的理解， 包括三个项目：a）对受影响的个人进行纵向观察，“自然史”研究， 扩大对挖掘编码临床数据财富的关注，以发现UCD中的新发病率; B）临床 了解癫痫发作活动的后果并确定潜在神经保护治疗的研究 高氨血症危象期间的方法;和c）对肝脏发育的观察性研究 随着时间的推移，UCD患者的功能障碍和障碍，包括定义肝纤维化的生物标志物。 2)为了培养下一代罕见病研究人员的发展，通过培训这仍然- 新生干部成为专家的表现团队科学临床调查罕见的遗传 疾病，尤其是UCD。 3)通过执行试点/可行性临床研究项目，确定有前途的新方法，以UCD护理 这将部署最先进的方法和技术，以监测和跟踪病人在诊所和 部署技术以实现远程观测。 4)通过为所有人提供方便的信息来传播知识并改善UCD的护理 其努力将影响结果的个人，包括研究人员（基础和临床），医生， 联盟医疗保健专业人员通过专业会议和listservs，我们的网站，播客和网络研讨会。的 对联盟的重要性还将是向患者、家属、 政府和公众。该联盟将通过UCDC的年度 通讯、公共网站、会议介绍和出版物。

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.