NEUROLOGICAL DISEASES DUE TO INBORN ERRORS OF METABOLISM

先天性代谢缺陷导致的神经系统疾病

• 批准号: 8171638
• 负责人: Juan M. Pascual
• 金额: $ 1.05万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8171638
• 关键词: Affect; Aftercare; Autistic Disorder; Biopsy; Blood Tests; Brain; Carbohydrates; Child; Childhood; Clinical Trials; Computer Retrieval of Information on Scientific Projects Database; DNA; Detection; Development; Diagnosis; Disease; Epilepsy; Evaluation; Failure; Fatty acid glycerol esters; Funding; Future; Grant; Growth and Development function; Human; Image; Inborn Errors of Metabolism; Institution; Life; Magnetic Resonance Imaging; Measurement; Measures; Medical center; Mental Retardation; Metabolic; Metabolism; Methods; Mitochondria; Mitochondrial Diseases; Molecular Abnormality; Muscle; Neurologic Examination; Nuclear Magnetic Resonance; Operative Surgical Procedures; Organ; Performance; Relative (related person); Research; Research Personnel; Resources; Risk; Sampling; Source; Surrogate Markers; Techniques; Testing; Tissues; United States National Institutes of Health; base; comparison group; design; disability; human disease; improved; nervous system disorder; neurobehavioral; new technology; protein metabolism

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. A major challenge to understanding human metabolism is posed by the absence of methods designed to investigate living tissues and organs directly. Until now, most studies have been conducted using surrogate markers of metabolism, such as blood tests, or have utilized samples obtained through biopsies or other surgical procedures. These difficulties are compounded when repeated measurements are needed (for example, to assess changes after treatment, or to understand growth and development) or when confronted with newly recognized or poorly-understood human disease states. Many types of childhood epilepsy, mental retardation, autism and other common forms of neurobehavioral disability are now thought to be manifestation of genetic abnormalities of fat, carbohydrate and protein metabolism that affect brain development and function. Most of these diseases remain understudied and, as a consequence, treatments are necessarily unsatisfactory. We propose to combine the resources of Children's Medical Center with novel technology developed at the UT Southwestern Clements Advanced Imaging Research Center to measure metabolism in the muscles of children by NMR (nuclear magnetic resonance) techniques, the same method on which routine MRI studies are based. Children afflicted by mitochondrial diseases capable of cooperating with the performance of an MRI will be invited to participate (together with a normal comparison group) on the basis of DNA and other tests demonstrative of a mitochondrial disease and will be additionally assessed using scored physical and neurological examinations and brain MRI. We anticipate that these studies will a) help us better understand the mechanisms of mitochondrial and related energy failure diseases, b) allow us to re-define these diseases on the basis of metabolic flux and muscle content measurements, c) improve the diagnosis of these disorders, including the detection of at-risk carrier relatives, and d) identify potential quantifiable markers for the conduct and evaluation of future clinical trials.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目及 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 缺乏直接研究活体组织和器官的方法是理解人类新陈代谢的一个主要挑战。到目前为止，大多数研究都是使用新陈代谢的替代标志物进行的，例如血液测试，或者利用通过活检或其他外科手术获得的样本。当需要重复测量（例如，评估治疗后的变化，或了解生长和发育）或面对新认识或知之甚少的人类疾病状态时，这些困难会变得更加复杂。许多类型的儿童癫痫、智力低下、自闭症和其他常见形式的神经行为障碍现在被认为是影响大脑发育和功能的脂肪、碳水化合物和蛋白质代谢遗传异常的表现。大多数这些疾病仍未得到充分研究，因此治疗效果必然不令人满意。我们建议将儿童医学中心的资源与 UT 西南克莱门茨高级成像研究中心开发的新技术相结合，通过 NMR（核磁共振）技术测量儿童肌肉的新陈代谢，这与常规 MRI 研究所采用的方法相同。患有线粒体疾病且能够配合 MRI 表现的儿童将被邀请参加（与正常对照组一起）基于 DNA 和其他证明线粒体疾病的测试，并将使用评分的身体和神经系统进行额外评估检查和脑部 MRI。我们预计这些研究将a）帮助我们更好地了解线粒体和相关能量衰竭疾病的机制，b）使我们能够根据代谢通量和肌肉含量测量重新定义这些疾病，c）改进这些疾病的诊断d) 确定潜在的可量化标记，用于未来临床试验的进行和评估。