LIPOPROTEIN LIPASE DEFICIENCY AND HUMAN BRAIN FU

描述：（申请人的摘要）脂蛋白脂肪酶（LPL）起着 在血浆甘油三酯脂肪酸分布中起关键作用， 不同的组织 因此，怀疑LPL功能异常 与人类多种脂质相关疾病有关。 家族性 LPL缺乏症，如果不治疗，其特征是禁食 高乳糜微粒血症，严重腹痛，脾肿大，肝肿大， 发疹性黄瘤和胰腺炎。 加拿大法裔人口 魁北克被发现有最大的一组LPL缺乏的个人， 世界上，携带者的数量估计高达40分之一， 某些地区。 在魁北克患者中，LPL缺乏症是一种常染色体遗传性疾病， 由于编码序列中的不同突变而导致的隐性疾病 LPL基因。 前带分布研究表明突变P207 L 这是魁北克LPL缺乏症的主要原因， 法裔加拿大人 LPL以不同的浓度存在于不同的区域， 神经系统，虽然脑组织，作为一个整体，是不丰富的LPL 脂肪组织和肌肉。 考虑到LPL的中心地位 在脂质代谢中，它似乎很可能具有重要的 和特殊的功能，大脑，一个组织， 脂蛋白和必需脂肪酸的结构和功能。 在 鉴于在提供的实际和道德约束， 无法接近的人体组织，特别是大脑，我们计划研究 利用LPL缺乏小鼠模型研究LPL在神经系统中的作用 (cld/cld）结合LPL缺陷的血细胞的研究 人类病人 我们希望回答以下问题：（一）脂蛋白脂肪酶 缺乏导致大脑结构和/或功能改变 实验动物的细胞？ (b)大脑的这些变化是否反映了 在循环淋巴细胞和血小板中的相应参数？ (c)这些动物数据能否用于识别异常的可能标志物 在淋巴细胞和血小板中的脑功能 家族性LPL缺乏症 待检查的结构参数将包括膜组成 脂质、脂蛋白和脂肪酸以及膜流动性。 的 功能参数将包括突触体和血小板对 5-羟色胺和表达，在脑细胞和淋巴细胞， 某些选定的基因参与神经递质的代谢， 神经肽和大脑特异性蛋白质的形成。

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.