Pathophysiology and Treatment of Medium-Chain Acyl-CoA Dehydrogenase Deficiency

描述(由申请人提供)： 候选人是一名初级学术内科医生，接受过儿科学、遗传学和生化遗传学方面的培训，其长期目标是进行以患者为导向的研究，以改进先天性代谢错误(IEM)的治疗方法。该培训计划旨在使他能够通过一系列授课和独立学习机会以及指导以患者为导向的研究，过渡到作为一名研究人员的独立性，拥有与LEM相关的临床试验方面的专业知识。这项研究集中在中链酰辅酶A脱氢酶(MCAD)缺乏症，这是美国新生儿筛查项目确定的最常见的先天性代谢错误。针对MCAD缺陷提出的大多数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。两种最常用的治疗MCAD缺乏症的干预措施--补充L肉碱和特别是饮食减脂--尚未受到严格的研究。具体地说，所描述的研究将探索这样的假设：在MCAD缺乏治疗中，口服L-卡尼汀可以防止代谢失调，减少饮食脂肪不能提供可测量的保护，以及目前使用的治疗方法可能会产生意想不到的后果。此外，一种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，并且肉碱/酰肉碱通量缓冲和维持线粒体比率的能力丧失！游离辅酶A(CoA)到酰基辅酶A(CoA)导致与失代偿过程相关的游离辅酶A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L-卡尼汀和饮食脂肪限制的药理剂量的效用，MCAD用于监测罕见并发症的协作注册，以及一系列利用小鼠模型进行的生理和生化研究，这些问题在人体研究中无法安全地回答。这些研究将为美国每年300多名先天患有MCAD缺陷的儿童的管理提供具体的循证指南。这一职业发展奖提供了一个关键的机会，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，促进应聘者作为翻译研究人员的职业发展。

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.