DHA SYNTHESIS AND TRANSPORT IN PEX2-/-MOUSE

PEX2-/-小鼠中 DHA 的合成和运输

• 批准号: 6536270
• 负责人: Paul A. WATKINS
• 金额: $ 8万
• 依托单位: HUGO W. MOSER RES INST KENNEDY KRIEGER
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-05-01 至 2003-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6536270
• 关键词: biological models; brain; cell component structure /function; cerebrohepatorenal syndrome; developmental neurobiology; erythrocytes; fatty acid biosynthesis; fatty acid transport; gene expression; gene mutation; genetically modified animals; high performance liquid chromatography; infant animal; intraperitoneal injections; laboratory mouse; liver; microinjections; molecular pathology; neuropathology; omega 3 fatty acid; peroxisome; phospholipids; plasma; radiotracer; scintillation counter

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.

描述：（改编自申请人的描述）本研究将重点关注二十二碳六烯酸（22:6n-3，DHA）在大脑和肝脏中的代谢 PEX2 -/- 小鼠，人类过氧化物酶体生物发生障碍模型 齐薇格综合症（ZS）。 PEX2 -/- 小鼠神经元迁移异常 和与人类 ZS 相似的生化缺陷。 通常 22:6n-3 是 以高浓度存在于大脑和视网膜中。 它部分源自 饮食以及亚油酸 (18:3n-3) 的内源合成 一系列去饱和和延伸步骤。 虽然大多数这些反应 发生在微粒体中，最近的研究表明过氧化物酶体也 发挥着关键作用。 对浓缩皮肤成纤维细胞的研究表明 24:6n-3 是 22:6n-3 的直接前体，即最后的链缩短步骤 发生在过氧化物酶体中，而成纤维细胞中缺乏此步骤 ZS 患者。 22：大脑、肝脏、红细胞中的 6n-3 水平降低 和ZS患者的血浆。 口服 22:6n-3 可使血浆正常化 水平和轶事报告表明它可以改善大脑和视网膜 功能。 研究人员的初步研究表明22:6n-3 PEX2-/- 小鼠大脑缺陷。 他们提议审查 通过比较 22:6n-3 合成和 22:6n-3 来了解这种还原的机制 转运到 PEX2 -/- 小鼠和对照同窝小鼠的大脑中。 合成 将通过测量 22:6n-3 的标记后进行体内研究 腹膜内和颅内注射远程前体 [1-14C] 18:3n-3 和 [1-14C] 22:5n-3 是商业上最直接的前体 可用的。 腹膜内与颅内结果比较 注射将允许评估运输。 体内研究将 辅以具有相同放射性标记的体外匀浆研究 前体。 PEX2 -/- 小鼠大脑中 22:6n-3 代谢的研究 提供评估 22:6n-3 缺陷在 ZS 中的作用的机会 治疗干预的潜在益处。