LIPOPROTEIN LIPASE DEFICIENCY AND HUMAN BRAIN FUNCTION

描述：(改编自申请者摘要)脂蛋白脂肪酶(LPL)发挥作用 对血浆脂蛋白的成熟和动态平衡起着至关重要的作用。 尽管导致酶失活的LPL基因突变已经被 在不同的民族中发现的，主要是进行了详细的研究 在法裔加拿大人中，因为有大量的人 在该人群中受LPL缺乏的影响。纯合子的发生率 在魁北克省东北部地区的LPL缺乏症是在 每10,000人中至少有1人，而普通人群的发病率低至1 一百万美元。据估计，LPL突变的携带者总数为 魁北克省至少有4.5万人。到目前为止的5个LPL突变中 在魁北克检测到一种(P207L)似乎是该人群独有的， 在其他地方找不到。 LPL似乎具有多种一般功能和组织特异性功能 在神经系统中。已观察到人类LPL缺乏会产生一种 神经缺陷的数量，包括记忆力丧失，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 LPL浓度。这种混乱造成的最严重后果是 发病机制可能与改变大小和 循环脂蛋白颗粒的组成及其形成 潜在的有毒脂类副产品。其中一项修改是增加了4倍 报道了溶血磷脂酰胆碱(Lyso-PTC)的浓度 刺激血液单个核细胞产生白介素2。 在提议的项目中，我们希望检验LPL缺陷的假设 干扰免疫系统和免疫系统之间的正常通讯过程 神经系统，由白介素所调节，通过结构和 血液单个核细胞和脑细胞的功能改变。我们的 实验将使用来自LPL的血细胞和血浆进行 缺乏和正常的加拿大法裔受试者，他们的基因和表型是 已经详细地刻画了。需要大脑的活体实验 组织将使用LPL基因敲除的转基因小鼠进行。

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.