Attenuating sterol synthesis in WT and NPC mice brains

描述(由申请人提供)：我们的长期目标是在胆固醇代谢和大脑神经病理之间提供新的和机械的联系。在本应用中，我们使用Niemann-Pick类型的C1型鼠标作为我们的模型系统。Niemann-Pick C型(NPC)病是一种致死性常染色体隐性遗传性神经内脏疾病，临床特征为进行性肝脾肿大和中枢神经系统(CNS)变性。它的特点是未酯化的胆固醇、鞘磷脂、糖脂和其他脂类在内体/溶酶体系统中的细胞积聚。目前，这种疾病还没有治愈的方法。胆固醇和/或糖鞘糖脂在大脑中的积累是否是这种疾病的主要致病因素尚不清楚，一直存在争议。我们最近证明了神经元胆固醇在非常年轻的NPC1小鼠的大脑中积累。我们现在建议用一种特定的胆固醇合成抑制剂(角鲨烯合成酶抑制剂；SSI)CP-340868(由辉瑞公司开发)治疗正常和NPC1小鼠。目的：探讨NPC1小鼠脑内胆固醇蓄积与神经节苷脂蓄积的关系。我们还将测试使用SSI作为治疗NPC1疾病的潜在药物疗法的可行性。我们的三个具体目标是： 具体目标1： A.比较SSICP-340858和HMG-CoA还原酶抑制剂Iovastatin阻断小鼠脑和肝脏胆固醇合成的量效关系。 B.检测SSICP-340868对正常和NPC1小鼠脑内胆固醇、糖脂和各种炎症细胞积聚的短期影响。 具体目的2：检测两种不同剂量的SSICP-340858对神经变性、浦肯野细胞丢失、体重减轻和运动控制缺失的中期影响，并检测正常和NPC1小鼠脑内不同区域的脂质积聚和炎细胞积聚。 具体目的3：观察2种不同剂量的SSICP-340868对正常和正常小鼠寿命的长期影响。

DESCRIPTION (provided by applicant): Our long-term goal is to provide new and mechanistic links between cholesterol metabolism and neuropathology in the brain. In this application, we use the Niemann-Pick type C1 mouse as our model system. Niemann-Pick type C (NPC) disease is a fatal autosomal recessive neurovisceral disorder characterized by clinically progressive hepatosplenomegaly and neurodegeneration in the central nervous system (CNS). It is characterized by the cellular accumulation of unesterified cholesterol, sphingomyelin, glycolipids, and other lipids within the endosomal/lysosomal system. Currently, there is no cure for this disease. Whether cholesterol accumulation and/or glycosphingolipid accumulation in the brain serves as a primary causative agent for this disease is not known, and has been under debate. We have recently demonstrated neuronal cholesterol accumulation in the brains of very young NPC1 mice. We now propose to treat normal and NPC1 mice with a specific cholesterol synthesis inhibitor (squalene synthase inhibitor; SSI) CP-340868 (developed by Pfizer, Inc.) to evaluate the relationship between cholesterol accumulation and ganglioside accumulation in the NPC1 mice brains. We will also test the feasibility of using SSI as a potential drug therapy to treat the NPC1 disease. Our 3 specific aims are: Specific Aim 1: a. To compare the dose effect of SSI CP-340858 and the HMG-CoA reductase inhibitor Iovastatin in blocking cholesterol synthesis, in the brains and the livers of mice. b. To examine the short-term effect of SSI CP-340868 on the accumulations of cholesterol, glycolipids, and various inflammatory cells in normal and NPC1 mice brains. Specific Aim 2: To examine the intermediate-term effect of SSI CP-340858 at 2 different doses on neurodegeneration, Purkinje cell loss, weight loss, and lack of motor control, and to examine the lipid accumulation and inflammatory cell accumulation in various regions of the brains in normal and NPC1 mice. Specific Aim 3: To examine the long-term effect of SSI CP-340868 at 2 different doses on life spans of normal and NPC1 mice.