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

罕见疾病临床研究联盟 (RDCRC) 的 RDCR 网络

• 批准号: 8325112
• 负责人: MARK L. BATSHAW
• 金额: $ 100.52万
• 依托单位: CHILDREN'S RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-30 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8325112
• 关键词: Adult; Anabolism; Argininosuccinate lyase deficiency; Biological Markers; Carbamyl Phosphate; Child; Citrullinemia; Clinical; Clinical Management; Clinical Research; Collaborations; Development; Disease; Enzymes; Evidence Based Medicine; Foundations; Functional Magnetic Resonance Imaging; Grant; Hyperammonemia; Hyperargininemia; Inborn Errors of Metabolism; Industry; Injury; Innovative Therapy; Liver Dysfunction; Longitudinal Studies; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Membrane Transport Proteins; Morbidity - disease rate; N acetyl L glutamate; N-carbamylglutamate; Natural History; Newborn Infant; Nitric Oxide; Ornithine carbamoyltransferase deficiency; Outcome; Pathogenesis; Patient advocacy; Patients; Phase; Pilot Projects; Rare Diseases; Research Personnel; Research Project Grants; Resources; Site; Syndrome; Synthase I; Training; Urea; Work; advocacy organizations; arginase; argininosuccinate synthase; career development; improved; mortality; neuromechanism; ornithinemia; programs; research study; tool; urea cycle; web site

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.

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具有高死亡率和发病率。UCD包括参与尿素生物合成的六种酶和两种膜转运蛋白中任何一种的缺陷：N-乙酰谷氨酸合酶（NAGS）缺陷;磷酸氨甲酰合酶I（CPSI）缺陷;鸟氨酸转氨甲酰酶缺陷（OTCD）;精氨酸琥珀酸合酶（AS）缺陷（瓜氨酸血症）;精氨基琥珀酸裂解酶（AL）缺乏（精氨酸琥珀酸尿症）;精氨酸酶（ARG）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。在上一个赠款期间，我们在罕见疾病临床研究网络（RDCRN）内创建了尿素循环障碍联盟（UCDC），并成功启动了四个研究项目，旨在了解UCD的自然史并开发新的治疗工具。目前，UCDC由8个美国研究中心组成，拥有一支由40多名研究人员和工作人员组成的跨学科团队。该联盟与国家尿素循环障碍基金会密切合作，该基金会是尿素循环障碍的患者倡导组织，并与行业合作开发针对这些疾病的创新疗法。在本申请中，我们提出了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，调查儿童和成人UCD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，以评估其在氨甲酰磷酸盐1和鸟氨酸转氨甲酰酶缺乏症患者中使尿素生成正常化的疗效;以及3） 使用结构MRI、功能MRI和磁共振波谱评估OTCD损伤的神经机制。在最初的试点项目中，我们将研究一氧化氮合成的底物可用性和相关的发病机制，在辅酶A酶和辅酶A琥珀酸裂解酶缺乏症。除了研究研究，我们将扩大和加强我们的教育和研究资源网站，并继续通过UCDC教育计划提供培训和职业发展机会。