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.

尿素周期疾病（UCD）是一组罕见但毁灭性的新陈代谢错误，从新生时期到成年后具有很高的死亡率和发病率。 UCD包括六种酶中的任何一种和参与尿素生物合成的膜转运蛋白的缺陷：N-乙酰基谷氨酸合酶（NAGS）；磷酸氨基甲酰基合酶I（CPSI）缺乏；鸟氨酸经氨基甲酸酶缺乏症（OTCD）； Argininoscication合酶（AS）缺乏症（瓜氨酸血症）； Argininoscicate裂解酶（Al）缺乏症（Argininosonoccinic酸尿）；精氨酸酶（ARG）缺乏症（精氨酸）；高足血症，高症血症，同核尿素（HHH）综合征；和柑橘类血症II。在上一个赠款期间，我们在稀有疾病临床研究网络（RDCRN）中创建了尿素周期疾病财团（UCDC），并成功启动了四个旨在了解UCD自然史和开发新的治疗工具的研究项目。目前，UCDC由8个美国网站组成，由40多名调查人员和员工组成。该财团与国家尿素周期障碍基金会（National Urea Cycor Disorders Foundation）紧密合作，该基金会是尿素周期疾病的患者倡导组织，并与行业合作开发了这些疾病的创新疗法。我们在此应用程序中提出了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，该研究调查了UCD儿童和成人的自然历史，发病率，死亡率和生物标志物； 2）对N-甲基谷氨酸酯进行LL/LLL相位试验，以评估其在磷酸氨甲磷酸氨基磷酸1和鸟氨酸经钙化酶缺乏症患者中的尿素发生术中的功效； 3） 使用结构MRI，功能性MRI和磁共振光谱评估OTCD损伤的神经机制。在拟议的初始试点项目中，我们将研究精氨酸酶和精氨酸酶裂解酶缺乏症中一氧化氮合成以及相关发病机理的底物可用性。除了研究研究外，我们还将扩展和增强我们的网站以供教育和研究资源，并继续通过UCDC教育计划提供培训和职业发展机会。