REGULATION OF CARNITINE TRANSPORT IN B-OXIDATION DEFECTS

B-氧化缺陷中肉碱转运的调节

• 批准号: 3245342
• 负责人: CHARLES ALFRED STANLEY
• 金额: $ 14.51万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-09-30 至 1997-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3245342
• 关键词: acyl coA dehydrogenases; acyl group; biological transport; carnitine; cellular respiration; enzyme inhibitors; fatty acid metabolism; hereditary carnitine deficiency myopathy; human subject; inborn biological transport disorder; inborn metabolism disorder; intracellular transport; membrane transport proteins; tissue /cell culture

Secondary carnitine deficiency is an important feature of 9 inherited disorders of mitochondrial fatty acid oxidation. The goal of this grant is to investigate the mechanism underlying this abnormality and its contribution to the pathophysiology of these disorders. Our hypothesis is that accumulations of fatty acylcarnitines, associated with blocks in fatty acid oxidation, lead to decreased tissue and plasma carnitine concentrations by inhibiting plasma membrane transport of free carnitine. This hypothesis will be tested by studies of 1) the interactions of individual acylcarnitines with the human muscle-kidney carnitine transporter in cultured skin fibroblasts; 2) the effects of genetic fatty acid oxidation defects on the function of this transporter both in affected patients and in their mutant fibroblasts; and 3) the in-vivo changes in tissue acyl-CoA and acylcarnitine concentrations induced by specific blocks in fatty acid beta-oxidation enzymes in experimental animals. In addition, we will investigate how carnitine transport and mitochondrial substrate oxidation are affected by a new genetic defect which blocks the transport of carnitine and acylcarnitines into mitochondria. These experiments will be facilitated by several unique resources, including the availability at The Children's Hospital of Philadelphia of patients with a large number of genetic disorders associated with secondary carnitine deficiency; analogs of Hypoglycin A which irreversibly inhibit specific fatty acyl-CoA dehydrogenase enzymes; and a repository of fibroblast cultures from over 500 patients with fatty acid oxidation disorders.

继发性肉碱缺乏症是 9 种遗传性疾病的重要特征 线粒体脂肪酸氧化障碍。 本次赠款的目标 的目的是研究这种异常现象的机制及其 对这些疾病的病理生理学的贡献。 我们的假设 是脂肪酰肉碱的积累，与阻断有关 脂肪酸氧化，导致组织和血浆肉碱减少 通过抑制游离肉碱的质膜转运来降低浓度。 该假设将通过以下研究进行检验：1） 单个酰基肉碱与人类肌肉-肾肉碱 培养的皮肤成纤维细胞中的转运蛋白； 2）遗传性脂肪的影响 酸氧化缺陷对该转运蛋白的功能的影响 受影响的患者及其突变的成纤维细胞； 3) 体内 引起的组织酰基辅酶A和酰基肉碱浓度的变化 实验中脂肪酸β-氧化酶的特定阻断 动物。 此外，我们将研究肉碱如何运输和 线粒体底物氧化受到新遗传缺陷的影响 它阻止肉碱和酰基肉碱转运到 线粒体。 这些实验将通过几个独特的方法来促进 资源，包括儿童医院的可用性 费城有大量遗传性疾病患者 与继发性肉碱缺乏有关；低甘氨酸A类似物 不可逆地抑制特定的脂肪酰辅酶A脱氢酶； 以及来自 500 多名脂肪肝患者的成纤维细胞培养物储存库 酸性氧化障碍。