The role of cholesterol metabolic enzyme CYP46A1 and its metabolite 24S-hydroxycholesterol in ischemic stroke.

项目摘要 本申请的总体目标是确定胆固醇代谢的作用， 酶CYP 46 A1及其代谢产物24 S-HC在缺血性卒中中的作用我们 中心假设是CYP 46 A1的激活导致24 S-HC的产生增加， 其通过NMDAR的增强作用导致缺血性脑损伤。来测试我们 假设，我们将使用体外和体内中风模型的组合，连同沿着 电生理学、钙成像和转基因小鼠，以追求以下三个具体 目标：目标1。确定CYP 46 A1在缺血性脑损伤中的作用;目的2.确定角色 24 S-HC在体外缺血性神经元损伤中的作用及其分子机制;定义 CYP 46 A1在缺血性脑损伤中作用的信号级联反应。成功 拟议的研究将确定胆固醇代谢酶CYP 46 A1及其 代谢产物24 S-HC在缺血性脑损伤中的作用。

PROJECT SUMMARY The overall objectives for this application are to determine the role of cholesterol metabolic enzyme CYP46A1 and its metabolite 24S-hydroxycholesterol (24S-HC) in ischemic stroke. Our central hypothesis is that activation of CYP46A1 results in increased production of 24S-HC, which contributes to ischemic brain injury through potentiation of NMDAR. To test our hypothesis, we will use a combination of in vitro and in vivo stroke models along with electrophysiology, calcium imaging and transgenic mice to pursue the following three specific aims: Aim 1. Determine the role of CYP46A1 in ischemic brain injury; Aim 2. Determine the role and molecular mechanism of 24S-HC in ischemic neuronal injury in vitro; Aim 3. Define the signaling cascade underlying the role of CYP46A1 in ischemic brain injury. Success of the proposed research will define the role of cholesterol metabolic enzyme CYP46A1 and its metabolite 24S-HC in ischemic brain injury.