病毒诱导神经元和中枢神经系统凋亡的机制-猫眼课题宝

病毒诱导神经元和中枢神经系统凋亡的机制

批准号：

7360281

负责人：

Kenneth L. Tyler

金额：

$24.78万

依托单位：

UNIVERSITY OF COLORADO DENVER

依托单位国家：

美国

项目类别：

财政年份：

2006

资助国家：

美国

项目状态：

已结题

起止时间：

2006-02-07 至 2010-12-31

来源：

https://reporter.nih.gov/project-details/7360281

关键词：

Adenoviruses Antisense Oligonucleotides Antiviral Therapy Apoptosis Apoptotic Brain Calpain Caspase Cell Death Cells Cellular Stress Central Nervous System Viral Diseases Cessation of life Cultured Cells Disease Disruption Dominant-Negative Mutation Encephalitis Endoplasmic Reticulum Epithelial Cells Event Gene Targeting In Vitro Infection Injury JUN gene Membrane Potentials Mitochondria Modeling Mus Neuraxis Neuroglia Neurons Organ Pathogenesis Pathway interactions Play Reoviridae Infections Reovirus Role Role playing therapy Signal Pathway Signal Transduction Small Interfering RNA Spinal Cord Stress Test Result Testing Tissues Translating Viral Virus Virus Diseases caspase 12 caspase-8 cell killing central nervous system injury cytochrome c design endonuclease G in vivo in vivo Model injured killings knowledge base mouse model neuron apoptosis neuron loss neurotropic virus novel prevent receptor reticulum cell stress-activated protein kinase 1

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Central nervous system (CMS) viral infections result from the capacity of viruses to injure neurons and other non-neuronal cells within the brain and spinal cord. A common mechanism by which a diverse group of neurotropic viruses injure target cells in the CMS is through apoptosis. Despite this fact, little is known about the precise mechanisms and specific cellular pathways leading to virus-induced apoptotic neural cell death. In this proposal we will utilize reovirus infection of primary neuronal cultures and a murine model of reovirus- induced encephalitis to examine the cellular pathways involved in virus-induced neuronal apoptosis. We have previously shown that death receptor apoptotic signaling contributes to reovirus-indced neuronal apoptosis. We hypothesize that both mitochondrial and endoplasmic reticulum cell stress apoptotic signaling pathways are also critical to reovirus-induced neuronal cell death. In Aim 1 we will determine the role played by endoplasmic reticulum (ER) and cellular-stress (GADD) pathways on reovirus-induced neuronal apoptosis and characterize the factors involved. In Aim 2 we will determine the role of mitochondria and mitochondrial factors in reovirus-induced apoptosis. Finally, in Aim 3 we will test the effects of manipulating apoptotic pathways on the pathogenesis of reovirus-induced CNS infection in vivo. A key aspect of the proposed studies is the ability to translate results obtained in studies of primary neuronal cultures in vitro, into an in vivo model of CNS viral infection. Reovirus infection was selected for these studies because it is one of the most extensively characterized models of virus-induced apoptosis and offers the advantage of a large pre- existing base of knowledge concerning viral determinants of apoptosis and the cellular pathways involved, as well as an easily accessible in mouse model of CNS apoptosis that allows rapid testing of results obtained in cell culture for their significance on the pathogenesis of CNS viral disease in vivo

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