Rare Diseases Clinical Research Consortia (RDCRC) for the RDCR Network

尿素循环障碍(UCD)是一组罕见但具有破坏性的先天性代谢错误，带有 从新生期到成年期的高死亡率和高发病率。UCD包括以下任何方面的缺陷 参与尿素生物合成的六种酶和两种膜转运体：N-乙酰谷氨酸合成酶 (NAGS)；氨基甲酰磷酸合成酶I(CPSI)缺乏症；鸟氨酸转氨甲基酶缺乏症(OTCD)； 精氨酸琥珀酸合成酶(AS)缺乏症(瓜氨酸血症)；精氨酸琥珀酸裂解酶(AL)缺乏症 (精氨酸尿症)；精氨酸酶(Arg)缺乏症(精氨酸血症)；高鸟氨酸血症 高瓜氨酸尿症(HHH)综合征；和瓜氨酸血症II型。在上一次赠款期间，我们有 在罕见病临床研究网络中创建了尿素循环障碍联盟(UCDC) (RDCRN)，并成功启动了四个旨在了解自然历史的研究项目 并开发新的治疗工具。目前，UCDC由8个美国站点组成，其中 由40多名调查人员和工作人员组成的跨学科团队。该财团与国家石油公司密切合作 尿素循环障碍基金会，尿素循环障碍患者倡导组织，并 与业界合作，为这些疾病开发创新的治疗方法。我们在此提出建议 申请3个完整的临床研究项目和1个试点项目。在临床项目中，我们将：1)继续 一项纵向研究，调查儿童和儿童的自然病史、发病率、死亡率和生物标志物 成人UCD；2)进行N-氨基甲酰谷氨酸的11/11期试验，以评估其正常化的效果 氨甲酰磷酸1和鸟氨酸转氨酶缺乏症患者的尿失禁； 应用结构MRI、功能MRI和磁共振评价OTCD损伤的神经机制 光谱学。在拟议的初步试验项目中，我们将研究合成一氧化氮的底物可用性。 精氨酸酶和精氨酸琥珀酸裂解酶缺乏症的相关发病机制。除 研究研究，我们将扩大和加强我们的教育和研究资源网站，以及 继续通过UCDC教育项目提供培训和职业发展机会。

Urea cycle disorders (UCD) are a group of 8 rare but devastating inborn errors of metabolism that carry a high mortality and morbidity from the newborn period through adulthood. UCD include deficiencies in any of the six enzymes and two membrane transporters involved in urea biosynthesis: N-acetylglutamate synthase (NAGS); Carbamyl phosphate synthase I (CPSI) deficiency; Ornithine transcarbamylase deficiency (OTCD); Argininosuccinate synthase (AS) deficiency (Citrullinemia); Argininosuccinate lyase (AL) deficiency (Argininosuccinic aciduria); Arginase (ARG) deficiency (Argininemia); Hyperornithinemia, hyperammonemia, homocitrullinuria (HHH) syndrome; and Citrullinemia type II. During the previous grant period we have created the Urea Cycle Disorders Consortium (UCDC) within the Rare Diseases Clinical Research Network (RDCRN) and have launched successfully four research projects aimed at understanding the natural history of UCD and developing new tools for treatment. Currently the UCDC consists of 8 U.S. sites with an interdisciplinary team of over 40 investigators and staff. The consortium works closely with the National Urea Cycle Disorders Foundation, the patient advocacy organization for urea cycle disorders and has collaboration with industry to develop innovative therapies for these disorders. We propose in this application 3 full clinical research projects and a pilot project. In the clinical projects we will: 1) Continue our longitudinal study that investigates the natural history, morbidity, mortality and biomarkers in children and adults with UCD; 2) Perform a Phase ll/lll trial of N-carbamylglutamate to assess its efficacy in normalizing ureagenesis in patients with carbamyl phosphate 1 and ornithine transcarbamylase deficiencies; and 3) Assess neural mechanisms of injury in OTCD using structural MRI, functional MRI, and magnetic resonance spectroscopy. In the proposed initial pilot project we will study substrate availability for nitric oxide synthesis and associated pathogenesis in arginase and argininosuccinate lyase deficiencies. In addition to the research studies, we will expand and enhance our website for educational and research resources and continue to provide training and career development opportunities through the UCDC educational programs.