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

项目总结 这项应用的总体目标是确定胆固醇代谢的作用 细胞色素P46A1及其代谢产物24S-羟基胆固醇(24S-HC)与缺血性卒中的关系我们的 中心假设是，CYP46A1的激活导致24S-HC的产生增加， 通过增强NMDAR参与缺血性脑损伤的发生。测试我们的 假设，我们将使用体外和体内中风模型的组合，以及 电生理、钙成像和转基因小鼠追求以下三个特异性 目的：目的1.确定CYP46A1在缺血性脑损伤中的作用；目的2.确定其在缺血性脑损伤中的作用 以及24S-HC在体外缺血性神经元损伤中的分子机制；目的3.确定 细胞色素P46A1在缺血性脑损伤中的作用。成功之路 拟议的研究将确定胆固醇代谢酶CYP46A1的作用及其 24S-HC代谢物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.