Investigations of Methylmalonic Acidemia and Related Dis

甲基丙二酸血症及相关疾病的调查

• 批准号: 7147996
• 负责人: Charles P Venditti
• 金额: --
• 依托单位: NATIONAL HUMAN GENOME RESEARCH INSTITUTE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7147996
• 关键词: cobalamin; disease /disorder model; genetically modified animals; human subject; laboratory mouse; medical complication; methylmalonic aciduria; vitamin B12 deficiency

This research study encompasses the hereditary methylmalonic acidemias (MMA) and cobalamin deficiency disorders. These metabolic disorders are genetically heterogeneous and collectively represent an important subset of the organic acidemias. They disorders are reviewed in references 2 through 4. We study the hereditary methylmalonic acidemias and cobalmin deficiency disorders via a translational approach that includes a clinical and metabolic evaluation of affected patients and the use animal models to examine the disorder in the laboratory. We review our approaches in reference 1. We have developed mouse and worm models of methylmalonic acidemia and have characterized both systems in the past year. The general goal of the research is to define the complications seen in the patients, replicate the findings in mice or other organisms and use the combined information to guide the development and testing of new therapies, such as gene and stem cell therapy. We maintain a mouse colony, use cell culture facilities, perform experiments with radioactive isotopes to study metabolism in cells and grow small roundworms in the laboratory. The human subject research is focused on assessing the natural history of methylmalonic acidemia in the United States to further understand the treatment, outcome and complications in this group of disorders. We have developed a patient database for outcomes research and have enrolled 40 participants in our clinical research studies since last year. We have studied the effects of solid organ transplantation on MMA, delineated a new neurologic syndrome in pateints who have suffered from a disease-related stroke and decribed a range of eye findings seen in one subset of patients. The patients are usually admitted to the NIH Clinical Research Center as inpatients for 3 to 4 days and undergo extensive metabolic testing. Many adults need magnetic resonance imaging and magnetic resonance spectroscopy of the central nervous system. We use a high field strength magnet ( 3 Telsa) for these studies.

这项研究涵盖遗传性甲基丙二酸血症 (MMA) 和钴胺素缺乏症。这些代谢紊乱具有遗传异质性，共同代表了有机酸血症的一个重要子集。参考文献 2 至 4 对这些疾病进行了综述。我们通过转化方法研究遗传性甲基丙二酸血症和钴胺缺乏症，其中包括对受影响患者进行临床和代谢评估，并使用动物模型在实验室检查该疾病。我们回顾了参考文献 1 中的方法。我们开发了甲基丙二酸血症的小鼠和蠕虫模型，并在过去的一年中对这两个系统进行了表征。该研究的总体目标是确定患者出现的并发症，在小鼠或其他生物体中复制研究结果，并利用综合信息指导新疗法的开发和测试，例如基因和干细胞疗法。我们维持小鼠群体，使用细胞培养设施，用放射性同位素进行实验来研究细胞的新陈代谢，并在实验室中培养小蛔虫。 人类受试者研究的重点是评估美国甲基丙二酸血症的自然史，以进一步了解这组疾病的治疗、结果和并发症。我们开发了一个用于结果研究的患者数据库，自去年以来已招募了 40 名参与者参加我们的临床研究。我们研究了实体器官移植对 MMA 的影响，描述了患有疾病相关中风的患者的一种新的神经系统综合征，并描述了在一部分患者中观察到的一系列眼部发现。患者通常会在 NIH 临床研究中心住院 3 至 4 天，并接受广泛的代谢测试。许多成年人需要中枢神经系统的磁共振成像和磁共振波谱。我们使用高场强磁铁 (3 Telsa) 进行这些研究。