DHA SYNTHESIS AND TRANSPORT IN PEX2-/-MOUSE

描述：(改编自申请者的描述)这项研究将集中在二十二碳六烯酸(22：6N-3，DHA)在大脑和肝脏中的代谢 PEX2-/-小鼠，一种人类过氧化物酶体生物发生障碍的模型 齐薇格综合征(Zellweger综合征，ZS)。PEX2-/-小鼠神经元迁移异常 以及类似于人类ZS的生化缺陷。通常22：6N-3是 在大脑和视网膜中浓度很高。它的部分来源是 饲料和内源合成亚油酸(18：3n-3)。 一系列的脱饱和度和伸长率步骤。尽管这些反应中的大多数 发生在微生物体中，最近的研究表明，过氧化物体也 起着关键作用。对成簇皮肤成纤维细胞的研究表明，24：6N-3 是22：6N-3的直接前驱，这最后的链缩短步骤 发生在过氧化酶体中，而这一步骤在成纤维细胞中是不足的 在ZS患者中。22：6N-3在脑、肝、红细胞中的水平降低 和ZS患者的血浆。口服22：6N-3使血浆正常化 水平和轶事报道表明，它可以改善大脑和视网膜 功能。调查人员的初步研究表明，22：6N-3 PEX2-/-小鼠的大脑缺陷。他们提议研究 通过比较22：6N-3合成和22：6N-3合成研究该还原反应的机理 在PEX2-/-小鼠和对照仔鼠中转运到大脑中。合成法 将通过测量22：6N-3的标记在体内进行研究 远端前体的腹膜内和颅内注射[1-14C] 18：3n-3和[1-14C]22：5n-3，是商业上最直接的前体 可用。腹膜腔内与颅内检查结果的比较 注资将允许对运输进行评估。体内研究将是 通过体外匀浆研究补充相同的放射性 先驱物。PEX2-/-小鼠脑内22：6n-3代谢的研究 提供机会评估22：6N-3缺乏在ZS和 治疗干预的潜在益处。

DESCRIPTION: (Adapted from the applicant's Description) This study will focus on the metabolism of docosahexaenoic acid (22:6n-3,DHA) in the brain and liver of the PEX2 -/- mouse, a model of the human peroxisome biogenesis disorder Zellweger syndrome (ZS). The PEX2 -/- mouse has abnormal neuronal migration and biochemical defects similar to those in human ZS. Normally 22:6n-3 is present in high concentration in brain and retina. It is derived in part from the diet and also by endogenous synthesis from linolic acid (18:3n-3) by a series of desaturation and elongation steps. Although most of these reactions take place in microsomes, recent studies indicate that the peroxisome also plays a key role. Studies in clutured skin fibroblasts indicate that 24:6n-3 is the immediate precursor of 22:6n-3, that this final chain shortening step takes place in the peroxisome, and that this step is deficient in fibroblasts of ZS patients. 22:6n-3 levels are reduced in the brain, liver, erythrocytes and plasma of ZS patients. Oral 22:6n-3 administration normalizes plasma levels and anecdotal reports suggest that it improves brain and retinal fuction. The investigators' preliminary studies have demonstrated 22:6n-3 deficiency in the brain of the PEX2-/- mouse. They proposed to examine the mechanism of this reduction by comparing 22:6n-3 synthesis and 22:6n-3 transport into the brain in PEX2 -/- mice and control littermates. Synthesis will be studied in vivo by measuring the labeling of 22:6n-3 after intraperitioneal and intracranial injections of the remote precursor [1-14C] 18:3n-3 and of [1-14C] 22:5n-3, the most direct precursor that is commercially available. Comparison of results of intraperitioneal and intracranial injection will permit assessment of transport. In vivo studies will be complemented by in vitro homogenate studies with the same radiolabled precursors. Studies of 22:6n-3 metabolism in the brain of the PEX2 -/- mouse provide the opportunity to evaluate the role of 22:6n-3 deficiency in ZS and the potential benefit for therapeutic intervention.