REGULATION OF CARNITINE TRANSPORT IN B-OXIDATION DEFECTS

继发性肉毒碱缺乏症是9种遗传性 线粒体脂肪酸氧化障碍。 这项资助的目的是 是研究这种异常的机制及其 对这些疾病的病理生理学的贡献。 我们的假设 是脂肪酰基肉毒碱的积累， 脂肪酸氧化，导致组织和血浆肉毒碱减少 通过抑制游离肉毒碱的质膜转运来提高浓度。 这一假设将通过以下研究进行检验：1） 单酰基肉毒碱与人肌肾肉毒碱 2）遗传性脂肪酸对皮肤成纤维细胞的影响; 酸氧化缺陷对这种转运蛋白的功能， 受影响的患者和他们的突变成纤维细胞;和3）体内 诱导的组织酰基辅酶A和酰基肉毒碱浓度的变化 脂肪酸β-氧化酶的特定块在实验 动物 此外，我们将调查如何肉毒碱运输和 线粒体底物氧化受到一种新的遗传缺陷的影响 阻断肉毒碱和酰基肉毒碱转运到 线粒体 这些实验将由几个独特的 资源，包括在儿童医院的可用性， 费城有大量的遗传性疾病患者 与继发性肉毒碱缺乏有关;低甘氨酸A类似物 其不可逆地抑制特定的脂肪酰辅酶A脱氢酶; 以及500多名脂肪肝患者的成纤维细胞培养物 酸氧化障碍

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.