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

胆固醇代谢酶CYP46A1及其代谢物24S-羟基胆固醇在缺血性脑卒中中的作用。

• 批准号: 10503336
• 负责人: TIANDONG LENG
• 金额: $ 35.5万
• 依托单位: MOREHOUSE SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10503336
• 关键词: Affect; Atherosclerosis; Binding; Biological Markers; Brain; Brain Ischemia; Calcium; Chemosensitization; Cholesterol; Cholesterol Homeostasis; Data; Development; Electrophysiology (science); Enzymes; Glucose; Glutamates; Goals; Hydroxycholesterols; Image; In Vitro; Intervention; Ischemic Brain Injury; Ischemic Neuronal Injury; Ischemic Stroke; Knock-out; Knockout Mice; Knowledge; Lead; Malignant Neoplasms; Measures; Metabolic; Molecular; Mus; N-Methyl-D-Aspartate Receptors; Nervous system structure; Neuronal Hypoxia; Neuronal Injury; Neurons; Oxygen; Pathologic; Pharmacology; Plasma; Production; Recovery; Research; Resistance; Role; Signal Transduction; Site; Sterols; Stroke; Structure-Activity Relationship; Testing; Therapeutic Intervention; Transgenic Mice; analog; base; cell type; deprivation; evidence base; excitotoxicity; in vivo; lipid metabolism; liquid chromatography mass spectrometry; nervous system disorder; new therapeutic target; positive allosteric modulator; post stroke; receptor function; small molecule; stroke intervention; stroke model; stroke outcome; stroke patient; success

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.

项目总结