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NEUROPROTECTIVE MECHANISMS OF STATINS IN NEURONS

他汀类药物对神经元的神经保护机制

基本信息

批准号：
7192132
负责人：
WELLINGTON GIBSON WOOD
金额：
$ 20.16万
依托单位：
UNIVERSITY OF MISSOURI-COLUMBIA
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-12-01 至 2011-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7192132
关键词：
3-hydroxy-3-methylglutaryl-coenzyme A AIDS Dementia Complex Alzheimer&apos s Disease Amyloid Amyloid beta-Protein Precursor Animals Antioxidants Apoptosis Apoptotic Astrocytes BCL2 gene Binding Blood Platelets Blood Vessels Calcineurin Cardiac Myocytes Cell Death Cell Nucleus Cell Survival Cell model Cell physiology Cells Cerebral cortex Characteristics Cholesterol Class Clinical Trials Collaborations Complement 3 Cyclodextrins Data EMSA Endothelin-1 Family Family member GTP-Binding Proteins Gene Expression Genes HA14-1 Hippocampus (Brain)Human In Vitro Indiana Inflammation Inflammatory Inflammatory Response Ischemia Ischemic Stroke Lead Lipids Lovastatin Membrane Messenger RNA Metabolism Mitochondria Multiple Sclerosis Mus N-Methylaspartate NADPH Oxidase Neuroblastoma Neurodegenerative Disorders Neuroglia Neurons Nuclear Nucleotides Oblimersen Oryctolagus cuniculus Oxidative Stress Oxidoreductase P2Y2 receptor Paper Pathway interactions Patients Personal Satisfaction Pharmaceutical Preparations Physiological reperfusion Play Pravastatin Preparation Process Production Promoter Regions Protein Biosynthesis Protein Family Protein Isoprenylation Protein Overexpression Proteins Protocols documentation Regulation Reperfusion Therapy Reporting Research Personnel Resources Role Signal Transduction Simvastatin Site Small Interfering RNA Smooth Muscle Myocytes Sterols T-Lymphocyte Testing Thinking Time Toxic effect Transcriptional Activation Transcriptional Regulation Transgenic Mice Up-Regulation Wood material apoptosis inducing factor astrogliosis atorvastatin brain tissue cell growth cell type excitotoxicity farnesyl pyrophosphate farnesylation geranylgeranyl pyrophosphate geranylgeranylation hypercholesterolemia in vivo inhibitor/antagonist innovation insight interest isoprenoid isoprenylation member mevalonate mitochondrial dysfunction mutant neuron apoptosis neuroprotection novel prenylation prevent programs research study rho rho GTP-Binding Proteins trafficking transcription factor

项目摘要

Our focus is on cholesterol-independent and dependent mechanisms whereby statins afford neuroprotection to cells undergoing oxidative stress. Statins reduce cholesterol levels but also they have cholesterol- independent mechanisms of action. Neuroprotective effects of statins could involve multiple pathways.We have discovered that statins altered expression of genes involved in apoptosis, cell growth, signaling and trafficking in the murine cerebral cortex. A novel finding was that simvastatin increased gene expressionand protein levels of Bcl-2 in vivo and in vitro. Bcl-2 and anti-apoptotic members of the Bcl-2 family play apivotal role in neuronal cell survival. Simvastatin also significantly increased ET-1 expression levels whose product is the precursor for the ET-1 protein. ET-1 is involved in transcriptional activation of Bcl-2. Preliminary data revealed that when Bcl-2 protein levels were experimentally reduced the neuroprotective effects of simvastatin to an Ap challenge were eliminated. We hypothesizethat: Simvastatin has both cholesterol- independent and-dependent mechanisms of action that are neuroprotective. Neuroprotective mechanisms are due to regulation of apoptosis by Bcl-2 family members, including the transcriptional regulation of Bcl-2 by ET-1/calcineurin/NFAT-dependent pathways and inhibition of Rac1 geranylgeranylation. These hypotheses will be testing primarily in mouse primary cortical and hippocampal neurons. Aim 1. Determine Bcl-2 and Bax gene expression and protein levels in neurons pretreated with simvastatin and challenged by A(Jor NMDA. Determine if simvastatin-induced increasein Bcl-2 inhibits translocation of apoptosis -inducing factor induced by Ap or NMDA from the mitochondria to the nucleus in neurons. Examine whether suppression of Bcl-2 gene expression or inactivation of the protein diminishes neuroprotective effects of simvastatin in neuroblastoma cells treated with Ap or NMDA. Aim 2. Determine if ET-1 increases Bcl-2 gene expression and protein levels in neurons challenged with Ap or NMDA. Evaluate if ET-1/calcineurin induces NFAT to the nucleus, binding to the NFAT sites on the Bcl-2 promoter region and increases Bcl-2 gene expression in neurons. Determine if suppression of ET-1 expression reduces simvastatin-induced stimulation of Bcl-2 gene expression and protein levels and neuroprotection when challenged by Ap or NMDA in human neuroblastoma cells. Aim 3. Determine if lowering cholesterol levels directly by cyclodextrin increases Bcl-2 and ET-1 gene expression andprotein levels in neurons and if neuroprotective. Evaluate if Bcl-2 and ET-1 gene expression and protein levels and neuroprotection are increased when farnesylation and geranylgeranylation are inhibited by non-statin inhibitors in neurons. Determine if simvastatin-induced stimulation of Bcl-2 and ET-1 gene expression and protein levels and neuroprotection can be inhibited by isoprenoids in neurons.

我们的重点是胆固醇独立和依赖机制，他汀类药物提供神经保护