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

尿素循环障碍（UCD）是一组8种罕见但破坏性的先天性代谢缺陷， 从新生儿期到成年期的高死亡率和发病率。UCD包括任何缺陷 参与尿素生物合成的六种酶和两种膜转运蛋白：N-乙酰谷氨酸合酶 （NAGS）;磷酸氨甲酰合酶I（CPSI）缺乏;鸟氨酸转氨甲酰酶缺乏（OTCD）; 精氨酸琥珀酸合酶（AS）缺乏症（瓜氨酸血症）;精氨酸琥珀酸裂解酶（AL）缺乏症 （精氨酸琥珀酸尿症）;精氨酸酶（ARG）缺乏（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II型瓜氨酸血症。在上一个资助期内， 在罕见疾病临床研究网络内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 UCD和开发新的治疗工具。目前，UCDC由8个美国站点组成， 由40多名调查员和工作人员组成的跨学科小组。该联盟与国家 尿素循环障碍基金会，尿素循环障碍的患者倡导组织， 与业界合作，为这些疾病开发创新疗法。我们在此建议 申请3个完整的临床研究项目和一个试点项目。在临床项目中，我们将：1）继续我们的 纵向研究，调查儿童的自然史、发病率、死亡率和生物标志物， 2）进行N-氨甲酰谷氨酸盐的II/III期试验，以评估其在正常化中的功效 氨甲酰磷酸1和鸟氨酸转氨甲酰酶缺乏症患者的尿素生成;以及3） 使用结构MRI、功能MRI和磁共振评估OTCD损伤的神经机制 谱在建议的初步试点项目中，我们将研究一氧化氮合成的底物可用性 以及与琥珀酸脱氢酶和氨基琥珀酸裂解酶缺乏相关的发病机制。除了有 研究，我们将扩大和加强我们的网站的教育和研究资源， 继续通过UCDC教育计划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.