Clinical-Res-Project1

临床研究项目1

• 批准号: 10670158
• 负责人: Susan A. Berry
• 金额: $ 67.3万
• 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 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10670158
• 关键词: Address; Adolescence; Adult; Affect; Age; Anabolism; Argininosuccinate lyase deficiency; Berry; Biological Markers; Carbamyl Phosphate; Caring; Child; Citrullinemia; Classification; Clinical; Clinical Data; Clinical Research; Clinical Trials; Clinical assessments; Collaborations; Data; Data Collection; Data Element; Data Set; Decision Making; Detection; Disease; Disease Progression; Effectiveness of Interventions; Enrollment; Enzymes; Etiology; Experimental Designs; Frequencies; Functional disorder; Funding; Future; Genotype; Goals; Grant; Growth and Development function; Health; Health Status; Hyperammonemia; Hyperargininemia; Inborn Errors of Metabolism; Individual; Infant; Intervention; Investigational Therapies; Knowledge; Late Effects; Life; Life Experience; Liver; Liver diseases; Long-Term Effects; Longevity; Longitudinal Studies; Measures; Medical; Membrane Transport Proteins; Mental Health; Metabolic; Mission; Mitochondria; Monitor; Morbidity - disease rate; Mothers; N acetyl L glutamate; Natural History; Neonatal; Newborn Infant; Nutritional status; Ornithine carbamoyltransferase deficiency; Outcome; Pathology; Patients; Persons; Pregnancy; Pregnancy Outcome; Prevalence; Quality of life; Rare Diseases; Recording of previous events; Recurrence; Research; Research Personnel; Research Project Grants; Risk Factors; Role; Seizures; Severities; Syndrome; Synthase I; U-Series Cooperative Agreements; Urea; Urea cycle disorders; Woman; argininosuccinate synthase; clinical encounter; clinical trial readiness; cognitive function; cohort; comorbidity; disorder subtype; follow-up; functional outcomes; improved; improved outcome; infant outcome; mortality; novel; ornithine transporter; ornithinemia; outcome prediction; predicting response; predictive marker; recruit; side effect; targeted treatment; treatment effect; treatment response; young adult

ABSTRACT - CLINICAL RESEARCH PROJECT 1 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 deficiency (NAGSD); Carbamyl phosphate synthase I deficiency (CPSID); Ornithine transcarbamylase deficiency (OTCD); Argininosuccinate synthase deficiency (ASSD) (Citrullinemia); Argininosuccinate lyase deficiency (ASLD) (Argininosuccinic aciduria); Arginase deficiency (ARGD) (Argininemia); Hyperornithinemia, hyperammonemia, homocitrullinuria (HHH) syndrome; and Citrullinemia type II (CITN). The Longitudinal Study (LS) is essential to the overall goals of the RDCRC Urea Cycle Disorders Consortium (UCDC) and is the basis of its research mission to address questions of pathophysiology, morbidity/mortality, as well as other outcomes of UCD including: (a) growth and development, (b) metabolic status, (c) nutritional status, (d) cognitive function, (e) treatment effects, (f) pregnancy outcomes of affected mothers and their children, (g) late effects and co- morbidities, and (h) quality of life/mental health status. The LS not only furnishes the clinical data to explore these issues but also enables the identification of critical biomarkers that predict outcome and response to treatment, serving as a basis for clinical trial readiness and experimental therapeutics. Critical to advancement in this group of rare diseases, during the current and previous grant periods the UCDC has successfully enrolled, classified, and characterized a large (> 800) patient cohort and used this data to expand knowledge of the natural history of UCD. The specific aims for the LS are to: 1) Examine the impact of UCD on outcomes of affected individuals throughout the lifespan. Questions to be addressed include: Do UCD and their associated treatments affect the growth and development of affected children and do these alter adult life functional outcomes of affected individuals? What is the contribution of the frequency and severity of hyperammonemic episodes in complicating outcomes? Does genotype impact outcome? What are the longer-term outcomes for affected infants into adolescence and young adulthood? Are women with UCD able to successfully and safely undergo pregnancy? How does the profile of recurring metabolic crisis evolve throughout the lifespan? Definition of these issues should allow future targeting of therapies towards improved outcomes and direct priorities in future clinical trials. 2) Establish the natural history of rare UCD subtypes and disorders with a particular focus on characterizing CPS1D, ARGD, CITR, HHH, and NAGSD and on differentiating the impact of uncommon subtypes of more common UCD. 3) Facilitate the study of co-morbidities including hepatic disease and seizures. Illuminating the role of these important but poorly recognized morbidities will be the focus of Projects 2 and 3 in this application and will rely, in part, on elements of data collected in the LS.

摘要-临床研究项目1 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 氨基甲酰磷酸合成酶I缺乏症 缺乏症（OTCD）;精氨基琥珀酸合酶缺乏症（ASSD）（瓜氨酸血症）;精氨基琥珀酸裂解酶 缺乏症（ASLD）（精氨酸琥珀酸尿症）;精氨酸酶缺乏症（ARGD）（精氨酸血症）;高鸟氨酸血症， 高氨血症、高瓜氨酸尿（HHH）综合征;和瓜氨酸血症II型（CITN）。纵向研究 (LS)对于RDCRC尿素循环障碍联盟（UCDC）的总体目标至关重要， 其研究使命是解决病理生理学、发病率/死亡率以及其他结果的问题 包括：（a）生长和发育，（B）代谢状态，（c）营养状态，（d）认知功能， (e)治疗效果，（f）受影响母亲及其子女的妊娠结局，（g）晚期效应和共同效应， 发病率，和（h）生活质量/心理健康状况。LS不仅收集了临床数据， 这些问题，而且还能够识别关键的生物标志物，预测结果和反应， 治疗，作为临床试验准备和实验治疗的基础。对进步至关重要 在这组罕见疾病中，在当前和以前的资助期间，UCDC成功地招募了， 分类，并描述了一个大的（> 800）患者队列，并使用这些数据来扩大自然的知识， UCD的历史 LS的具体目标是：1）检查UCD对受影响个人结果的影响 在整个生命周期中。需要解决的问题包括：UCD及其相关治疗是否影响 受影响儿童的生长和发育，这些是否会改变受影响儿童的成年生活功能结果 个人？高氨血症发作的频率和严重程度在并发症中的作用是什么？ 成果？基因型影响结果吗？受影响的婴儿进入 青春期和青年期？患有UCD的女性能够成功和安全地怀孕吗？ 在整个生命周期中，反复发生的代谢危机是如何演变的？这些问题的定义 应该允许未来的治疗目标朝着改善的结果和直接优先在未来的临床试验。 2)建立罕见的UCD亚型和疾病的自然史，特别注重表征 CPS 1D、ARGD、CITR、HHH和NAGSD，以及区分更多不常见亚型 普通的ucd 3)促进共病研究，包括肝病和癫痫发作。照亮 这些重要但认识不足的疾病的作用将是本申请项目2和项目3的重点 并且将部分地依赖于在LS中收集的数据元素。