Pathophysiology and treatment of medium-chain acyl-CoA dehydrogenase deficiency

中链酰基辅酶A脱氢酶缺乏症的病理生理学和治疗

• 批准号: 7673387
• 负责人: SHAWN E MCCANDLESS
• 金额: $ 12.91万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-20 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7673387
• 关键词: Acute; Acyl Coenzyme A; Address; Affect; Animal Model; Benign; Biochemical; Biochemical Genetics; Brain Injuries; Buffers; Carnitine; Child; Clinical; Clinical Trials; Clinical Trials Design; Coenzyme A; Data Analyses; Development; Diet; Dietary Fats; Disease; Dose; Early Diagnosis; Eating Behavior; Emergency Care; Esterified Fatty Acids; Ethical Issues; Experimental Animal Model; Family; Fatty acid glycerol esters; Feeding behaviors; Fostering; Functional disorder; Genetic; Goals; Hospitalization; Human; Inborn Errors of Metabolism; Individual; Intervention; Intervention Studies; K-Series Research Career Programs; Lead; Learning; Levocarnitine; Liver; Measurable; Measures; Medical; Mentors; Metabolic; Metabolic stress; Metabolism; Mitochondria; Monitor; Mus; Muscle; Neonatal Screening; Oral; Outcome; Patients; Pattern; Pediatrics; Physicians; Physiological; Plasma; Process; Recommendation; Registries; Relative (related person); Research; Research Personnel; Risk; Sampling; Series; Supplementation; Surveys; Testing; Therapeutic; Therapeutic Effect; Therapeutic Intervention; Time; Tissues; Training; Training Programs; United States; Urine; Variant; Work; acyl-CoA dehydrogenase; acylcarnitine; career development; control trial; design; evidence base; evidence based guidelines; experience; human subject; improved; mouse model; patient oriented research; programs; prospective; research study; response; statistics; treatment effect

DESCRIPTION (provided by applicant): The candidate is a junior academic physician, trained in Pediatrics, Genetics and Biochemical Genetics whose long term goal is to conduct patient oriented research that will improve therapies for inborn errors of metabolism (IEM). The training program is designed to enable him to transition to independence as a researcher with expertise in clinical trials related to lEMs through a series of didactic and independent learning opportunities and mentored patient oriented research. This research centers on medium-chain acyl-CoA dehydrogenase (MCAD) deficiency, the most common inborn error of metabolism identified by newborn screening programs in the United States. Scientific evidence is lacking for most of the interventions and management recommendations made for MCAD deficiency, therefore evidence-based management is impossible at this time. Two of the most commonly used interventions for management of MCAD deficiency, supplementation with L-carnitine and dietary fat reduction in particular, have not been subjected to rigorous study. Specifically, the studies described will explore the hypotheses that in MCAD deficiency therapy with oral L-carnitine can protect against metabolic decompensation, that reduction in dietary fat does not provide measurable protection, and that the therapies currently used may have unexpected consequences. Further, a mouse model addresses the hypotheses that there is a predictable physiological and metabolic pattern to the process of metabolic decompensation and that loss of the capacity of carnitine/acylcarnitine flux to buffer and maintain the ratio of mitochondria! free coenzyme A (CoA) to acyl-CoA leads to an acute state of relative insufficiency of free CoA associated with the decompensation process. The research plan describes a prospective clinical trial to test the utility of pharmacological doses of L-carnitine and dietary fat restriction, a collaborative registry for MCAD to monitor for rare complications, and a series of physiological and biochemical studies utilizing a mouse model for questions that cannot be safely answered in human studies. These studies will lead to specific evidenced-based guidelines for the management of the more than 300 children born with MCAD deficiency every year in the US. This career development award presents a key opportunity to foster the candidate's career development as a translational researcher through study of clinical trial design, data analysis and statistics, and ethical issues related to research with human subjects.

描述（由申请人提供）： 候选人是一名初级学术医生，在儿科，遗传学和生化遗传学方面接受过培训，其长期目标是进行以患者为导向的研究，以改善先天性代谢缺陷（IEM）的治疗方法。该培训计划旨在使他能够通过一系列教学和独立学习机会以及指导以患者为导向的研究，作为一名具有LEM相关临床试验专业知识的研究人员过渡到独立。这项研究的中心是中链酰基辅酶A脱氢酶（MCAD）缺乏症，这是美国新生儿筛查计划确定的最常见的先天性代谢缺陷。大多数针对MCAD缺陷的干预措施和管理建议缺乏科学证据，因此目前不可能进行循证管理。两个最常用的干预措施管理MCAD缺乏症，补充左旋肉碱和饮食脂肪减少，特别是，还没有受到严格的研究。具体而言，所描述的研究将探讨以下假设：在MCAD缺乏症治疗中，口服左旋肉碱可以防止代谢失代偿，减少膳食脂肪不能提供可测量的保护，目前使用的疗法可能会产生意想不到的后果。此外，小鼠模型解决了这样的假设，即代谢失代偿过程存在可预测的生理和代谢模式，并且肉毒碱/酰基肉毒碱通量缓冲和维持线粒体的比率的能力的丧失。游离辅酶A（CoA）转化为酰基-CoA导致与代偿失调过程相关的游离CoA相对不足的急性状态。该研究计划描述了一项前瞻性临床试验，以测试药理学剂量的L-肉碱和饮食脂肪限制的效用，一项用于MCAD的合作登记以监测罕见并发症，以及一系列生理和生化研究，利用小鼠模型来解决人类研究中无法安全回答的问题。这些研究将为美国每年300多名患有MCAD缺陷的儿童的管理提供具体的循证指南。该职业发展奖提供了一个重要的机会，通过研究临床试验设计，数据分析和统计，以及与人类受试者研究相关的伦理问题，促进候选人作为转化研究人员的职业发展。