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: 7932561
• 负责人: MARK L. BATSHAW
• 金额: $ 30万
• 依托单位: CHILDREN'S RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7932561
• 关键词: Rare; Diseases; Clinical; Research; Consortia

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天生代谢错误，携带的代谢错误 从新生时期到成年期的高死亡率和发病率。 UCD在任何一项中都包括缺陷 参与尿素生物合成的六种酶和两个膜转运蛋白：N-乙酰谷氨酸合酶 （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）；精氨酸酶裂解酶（Al）缺陷 （Argininosonoccinic酸尿）；精氨酸酶（ARG）缺乏症（精氨酸）；高义血症，高症血症， 同尿症（HHH）综合征；和柑橘类血症II。在上一个赠款期间，我们有 在稀有疾病临床研究网络中创建了尿素周期疾病财团（UCDC） （RDCRN）并已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个美国网站组成 跨学科团队由40多名调查员和员工组成。该财团与国家紧密合作 尿素周期疾病基金会，尿素周期疾病的患者倡导组织 与行业合作，为这些疾病开发创新疗法。我们建议 应用3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 纵向研究研究了儿童的自然历史，发病率，死亡率和生物标志物 成年人患有UCD； 2）执行N-甲基谷氨酸n-甲基谷氨酸的相位LL/LLL试验，以评估其在归一化方面的功效 磷酸氨基甲酰基1和鸟氨酸经氨基甲酶缺乏症患者的尿素发生； 3） 使用结构MRI，功能MRI和磁共振评估OTCD损伤的神经机制 光谱法。在拟议的初始试点项目中，我们将研究一氧化氮合成的底物可用性 精氨酸酶和精氨酸酸酯裂解酶缺陷中的相关发病机理。除了 研究研究，我们将扩展和增强我们的网站以获取教育和研究资源以及 继续通过UCDC教育计划提供培训和职业发展机会。