REGULATION OF CARNITINE TRANSPORT IN B-OXIDATION DEFECTS

继发性肉碱缺乏是遗传性的一个重要特征 线粒体脂肪酸氧化紊乱。这笔赠款的目的是 是调查这种反常现象背后的机制及其 对这些疾病的病理生理学的贡献。我们的假设 脂肪酰卡尼汀的积聚，与 脂肪酸氧化，导致组织和血浆肉碱减少 浓度通过抑制细胞膜上游离肉碱的转运来实现。 这一假设将通过1)相互作用的研究来检验 人肌肉-肾肉碱的个体酰化肉碱 皮肤成纤维细胞中的转运蛋白；2)遗传性脂肪的影响 这一转运蛋白功能上的酸氧化缺陷 受影响的患者及其突变的成纤维细胞；以及3)体内 大鼠组织中乙酰辅酶A和乙酰肉碱浓度的变化 实验中脂肪酸β-氧化酶的特异性阻断 动物。此外，我们将调查肉碱是如何运输和 线粒体底物氧化受到一种新的遗传缺陷的影响 阻止肉碱和酰基肉碱的运输进入 线粒体。这些实验将由几个独特的 资源，包括儿童医院提供的 费城的大量遗传性疾病患者 与继发性肉碱缺乏症有关；低血糖A的类似物 不可逆地抑制特定的脂肪酰辅酶A脱氢酶； 以及500多名肥胖症患者的成纤维细胞培养库 酸氧化紊乱。

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.