Attenuating sterol synthesis in WT and NPC mice brains

描述（由申请人提供）：我们的长期目标是提供脑中胆固醇代谢和神经病理学之间的新的机制联系。在这个应用中，我们使用Niemann-Pick型C1小鼠作为我们的模型系统。C型尼曼-匹克病（Niemann-Pick type C，NPC）是一种致死性常染色体隐性遗传神经内脏系统疾病，临床表现为进行性肝脾肿大和中枢神经系统（CNS）神经退行性变。其特征在于未酯化胆固醇、鞘磷脂、糖脂和其他脂质在内体/溶酶体系统内的细胞蓄积。目前，没有治愈这种疾病的方法。脑中胆固醇蓄积和/或鞘糖脂蓄积是否是该疾病的主要致病因素尚不清楚，并且一直处于争论之中。我们最近已经证明了神经元胆固醇积累在非常年轻的NPC 1小鼠的大脑。我们现在提出用特异性胆固醇合成抑制剂（角鲨烯合成酶抑制剂; SSI）CP-340868（由Pfizer，Inc.评价NPC 1小鼠脑中胆固醇蓄积和神经节苷脂蓄积之间的关系。我们还将测试使用SSI作为治疗NPC 1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SSI CP-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剂量效应。 B.检查SSI CP-340868对正常和NPC 1小鼠脑中胆固醇、糖脂和各种炎性细胞蓄积的短期影响。 具体目标二：检查2种不同剂量的SSI CP-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，并检查正常和NPC 1小鼠大脑各区域中的脂质蓄积和炎症细胞蓄积。 具体目的3：检查2种不同剂量的SSI CP-340868对正常和NPC 1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.