LIPOPROTEIN LIPASE DEFICIENCY AND HUMAN BRAIN FU

描述：(申请者摘要)脂蛋白脂肪酶(LPL)发挥重要作用 在血浆甘油三酯脂肪酸分布中的关键作用 不同的组织。因此，LPL功能异常是可疑的 与人类多种与脂质有关的疾病有关。家族性 LPL缺乏，如果不治疗，其特征是禁食 高乳糜微球血症，剧烈腹痛，脾大，肝大， 发作性黄瘤和胰腺炎。年的法裔加拿大人口 魁北克被发现拥有最大的LPL缺陷个体群体 全球，据估计，全球航空公司的数量高达40% 某些地区。在魁北克患者中，LPL缺乏是一种常染色体 编码序列不同突变导致的隐性疾病 低密度脂蛋白基因。先证者分布研究表明突变P207L 魁北克LPL不足的主要原因几乎完全是 法裔加拿大人。 LPL在不同地区以不同的浓度存在 神经系统，尽管作为一个整体，大脑组织中LPL含量不是很高 脂肪组织和肌肉。关于物流中心地位的思考 在脂质代谢中，它很可能有一个重要的 以及大脑的特殊功能，这是一种关键依赖于 脂蛋白和必需脂肪酸对其结构和功能的影响。在……里面 关于可获得的实际和道德限制的观点 不可触及的人体组织，特别是大脑，我们计划研究 利用LPL缺乏症小鼠模型研究LPL在神经系统中的作用 (cld/cld)结合LPL缺陷血细胞的研究 人类病人。 我们希望回答以下问题：(A)脂蛋白脂肪酶 缺乏会导致大脑结构和/或功能的改变 实验动物的细胞？(B)这些变化是否反映在大脑中？ 循环中的淋巴细胞和血小板中的相应参数？ (C)这些动物数据能否被用来确定异常的可能标志 受试者淋巴细胞和血小板的脑功能 家族性LPL缺乏症？ 要检查的结构参数将包括膜成分 脂类、脂蛋白和脂肪酸的含量以及膜流动性。这个 功能参数将包括突触体和血小板摄取 5-羟色胺及其在脑细胞和淋巴细胞中的表达 某些特定的基因参与神经递质的代谢和 在神经肽和大脑特定蛋白的形成中。

DESCRIPTION: (Applicant's Abstract) Liproprotein lipase (LPL) plays a crucial role in the distribution of plasma triglyceride fatty acids to different tissues. Abnormalities in LPL function are, therefore, suspected to be implicated in a variety of lipid related diseases in humans. Familial LPL deficiency, when untreated, is characterized by fasting hyperchylomicronemia, severe abdominal pain, splenomegaly, hepatomegaly, eruptive xanthomas and pancreatitis. The French-Canadian population in Quebec is found to have the largest group of LPL deficient individuals in the world, with the number of carriers estimated to be as high as 1 in 40 in certain regions. In Quebec patients, LPL deficiency is an autosomal recessive disorder resulting from different mutations in the coding sequence of the LPL gene. Proband distribution studies indicate that mutation P207L which is the major cause of LPL deficiency in Quebec is almost exclusively French-Canadian. LPL is present in variable concentrations in different regions of the nervous system, although the brain tissue, as a whole, is not as rich in LPL as the adipose tissue and muscle. Considering the central position of LPL in lipid metabolism, it appears very likely that it may have an important and special function in brain, a tissue which depends critically on lipoproteins and essential fatty acids for its structure and function. In view of the practical and ethical constraints in the availability of inaccessible human tissues, particularly brain, we plan to investigate the role of LPL in the nervous system by using a mouse model of LPL deficiency (cld/cld) in combination with studies of the blood cells of LPL deficient human patients. We hope to answer the following questions: (a) Does lipoprotein lipase deficiency lead to structural and/or functional alterations in the brain cells of experimental animals? (b) Are these alterations in brain reflected in corresponding parameters in the circulating lymphocytes and platelets? (c) Can these animal data be used to identify possible markers of abnormal brain function in the lymphocytes and platelets of human subjects suffering from familial LPL deficiency? The structural parameters to be examined will include membrane composition of lipids, liproproteins and fatty acids as well as membrane fluidity. The functional parameters will include synaptosomal and platelet uptake of serotonin and the expression, in the brain cells and in lymphocytes, of certain selected genes involved in the metabolism of neurotransmitters and in the formation of neuropeptides and brain specific proteins.