Clinical-Res-Project1

临床研究项目1

• 批准号: 10018948
• 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/10018948
• 关键词: Address; Adolescence; Adult; Affect; Age; Anabolism; Argininosuccinate lyase deficiency; Berry; Biological Markers; Carbamyl Phosphate; Caring; Child; Citrullinemia; Clinical; Clinical Data; Clinical Research; Clinical Trials; Clinical assessments; 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; Readiness; Recording of previous events; 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; 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 尿素周期障碍（UCD）是一组罕见但毁灭性的天生代谢错误 从新生时期到成年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 缺陷（NAGSD）;磷酸氨基磷酸合酶I缺乏症（CPSID）；鸟氨酸经钙基酶 缺陷（OTCD）; ArginInoscinate合酶缺乏症（ASSD）（瓜氨酸血症）；精氨酸酶裂解酶 缺乏症（ASLD）（Argininosuccinic酸尿）；精氨酸酶缺乏症（ARGD）（精氨酸）；高义义血症， 高症血症，同尿酸（HHH）综合征；和II型瓜氨酸血症（CITN）。纵向研究 （LS）对于RDCRC尿素周期疾病联盟（UCDC）的总体目标至关重要，并且是基础 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 UCD包括：（a）增长和发展，（b）代谢状况，（c）营养状况，（d）认知功能， （e）治疗效应，（f）受影响母亲及其子女的妊娠结局， 病态和（H）生活质量/心理健康状况。 LS不仅提供临床数据以探索 这些问题，但还可以识别关键生物标志物，以预测结果和回应 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 在这一组罕见疾病中，在当前和以前的赠款期间，UCDC已成功入学， 分类并描述了一个大（> 800）患者队列，并使用这些数据来扩展自然知识 UCD的历史。 LS的具体目的是：1）检查UCD对受影响个体结果的影响 在整个生命周期中。要解决的问题包括：UCD及其相关治疗会影响 受影响儿童的成长和发展，并改变了受影响的成人生活功能结果 个人？高肌发作的频率和严重程度的贡献是什么 结果？基因型会影响结果吗？受影响婴儿的长期结局是什么 青春期和成年年轻？患有UCD的妇女是否能够成功，安全地怀孕？ 在整个生命周期中，复发代谢危机的概况如何发展？这些问题的定义 应该允许将来将疗法定位到未来临床试验中的改善结果和直接优先级。 2）建立稀有UCD亚型和疾病的自然史，特别着眼于表征 cps1d，argd，citr，hhh和nagsd，并区分不常见的亚型的影响 常见的UCD。 3）促进研究包括肝病和癫痫发作在内的合并症。照亮 这些重要但知名的病毒性的作用将是项目2和3的重点 并部分依赖于LS中收集的数据元素。