LIPOPROTEIN LIPASE DEFICIENCY AND HUMAN BRAIN FUNCTION

描述：（改编自申请人的摘要）脂蛋白脂肪酶（LPL）起作用 在血浆脂蛋白的成熟和稳态中起关键作用。 虽然LPL基因突变导致酶失活，但已经被证实是一种新的酶。 在不同的民族群体中发现， 在法裔加拿大人中，因为有大量的人 受LPL缺乏症的影响。纯合子的发生率 魁北克省东北部地区的LPL缺乏症 至少1/10，000，而一般人群的发病率低至1 一百万。LPL突变携带者的总数估计为 在魁北克省至少有四万五千人。在目前为止的5个LPL突变中 在魁北克检测到一种P207 L，似乎是该种群特有的， 在别处找不到。 LPL似乎具有多种一般和组织特异性功能 在神经系统中。已观察到人类LPL缺乏会产生 许多神经系统缺陷，包括记忆丧失，难以清除 思考和解决问题。这些函数通常与 海马体是大脑结构中含有最高的 LPL的浓度。这种疾病最严重的后果是， 发病机制可能与大小的改变有关， 循环脂蛋白颗粒的组成和形成 潜在的有毒脂质副产物。一个这样的修改是4倍增加 溶血磷脂酰胆碱（lyso-PTC）的浓度， 以刺激血液单核细胞产生白细胞介素。 在拟议的项目中，我们希望测试LPL缺乏的假设， 干扰免疫系统和细胞之间的正常通讯过程 神经系统，介导的白细胞介素，通过结构和 血液单核细胞和脑细胞的功能改变。我们 实验将使用来自LPL的血细胞和血浆进行 缺乏和正常的法裔加拿大人的基因型和表型， 已经详细描述了。需要大脑的体内实验 将使用LPL敲除的转基因小鼠进行组织移植。

DESCRIPTION: (adapted from applicant's abstract) Lipoprotein lipase (LPL) plays a crucial role in the maturation and homeostasis of plasma lipoproteins. Although LPL gene mutations, leading to inactivation of the enzyme, have been found in different ethnic groups, detailed studies have been carried out mainly among French-Canadians because of the large number of people that have been affected by LPL deficiency in this population. The incidence of homozygosity for LPL deficiency in the North-Eastern region of the Province of Quebec is at least 1 in 10,000 while the incidence in the general population is as low as 1 in 1,000,000. The total number of carriers for LPL mutations is estimated to be at least 45,000 in the province of Quebec. Of the 5 LPL mutations so far detected in Quebec, one (P207L) appears to be unique to this population and is not found elsewhere. LPL appears to have a variety of general as well as tissue specific functions in the nervous system. LPL deficiency in humans has been observed to produce a number of neurological defects, including memory loss, difficulty in clear thinking and problem solving. These functions are usually associated with the hippocampus which is one of the brain structures containing the highest concentrations of LPL. The most serious consequences of this disorder in regard to pathogenesis is probably related to modifications in the sizes and composition of circulating lipoprotein particles and the formation of potentially toxic lipid byproducts. One such modification is a 4 fold increase in the concentration of lyso-phosphatidylcholine (lyso-PTC) which is reported to stimulate the production of interleukins by blood mononuclear cells. In the proposed project, we wish to test the hypothesis that LPL deficiency interferes with the normal processes of communication between the immune and nervous systems, mediated by the interleukins, through structural and functional alterations of both the blood mononuclear cells and brain cells. Our experiments will be carried out using blood cells and plasma derived from LPL deficient and normal French Canadian subjects whose genotypes and phenotypes we have already characterized in detail. In vivo experiments requiring brain tissue will be performed using LPL knockout transgenic mice.