Role of Astrocyte Injury in Neuroprotection

星形胶质细胞损伤在神经保护中的作用

• 批准号: 7792397
• 负责人: MARTIN A. PHILBERT
• 金额: $ 51.92万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-06-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7792397
• 关键词: ATP phosphohydrolase; Acute; Address; Adenosine; Alzheimer' s Disease; Antimetabolites; Astrocytes; Ataxia; BCL1 Oncogene; Bax protein; Binding; Binding Proteins; Brain Stem; Calcium; Cell Death; Cell physiology; Cells; Cellular Morphology; Cessation of life; Chemicals; Coupled; Data; Dependency; Development; Dinitrobenzenes; Dissection; Dysesthesias; Energy Metabolism; Environment; Event; Exposure to; Extracellular Space; Foot Process; Foundations; Functional disorder; Funding; Gene Expression; Generations; Hemorrhage; Hereditary Disease; Homeostasis; Hour; Human; Imaging Techniques; Injury; Inner mitochondrial membrane; Intoxication; Isomerism; Laboratories; Lead; Lesion; Life; Maintenance; Measures; Mediating; Membrane; Membrane Potentials; Mitochondria; Modeling; Monitor; Morphology; Neocortex; Neuraxis; Neurons; Neuropil; Neurotoxins; Optics; Outcome; Oxidative Stress; Paralysed; Paresthesia; Parkinson Disease; Pathway interactions; Phase; Poisoning; Predisposition; Production; Protein Family; Proteins; Proto-Oncogene Proteins c-akt; Purinergic P1 Receptors; RNA Interference; Rattus; Reactive Oxygen Species; Research; Role; Series; Signal Pathway; Signal Transduction; Supporting Cell; Swelling; Syndrome; Techniques; Testing; Thiamine; Thiamine Deficiency; Three-Dimensional Image; Time; central nervous system injury; deafness; deprivation; environmental chemical; excitotoxicity; extracellular; injured; insight; mathematical model; member; mitochondrial membrane; mitochondrial permeability transition pore; nanoscale; neocortical; neuron loss; neuronal cell body; neuroprotection; neurotoxic; neurotoxicity; novel; paracrine; protein activation; public health relevance; receptor; receptor function; receptor-mediated signaling; research study; response

DESCRIPTION (provided by applicant): Astrocytes are an important component of the neuropil and their dysfunction has been associated with a variety of idiopathic and genetic diseases including Alzheimer's and Parkinson's disease and in energy deprivation syndromes such as thiamine deficiency and antimetabolite poisoning. The prevailing model of healthy astrocyte-neuron interaction is one of continuous and intimate physical contact between adjacent membranes that promotes neuronal homeostasis. While the loss of astrocytes in the neuropil is generally viewed as a negative event, we propose here that in the acute phases of intoxication loss of astrocytes may protect neurons against further injury mediated by release of adenosine. Specifically, in this proposal we hypothesize that DNB-induced oxidative stress in astrocytes induces the release of adenosine which in turn activates A1 receptors in neurons via paracrine mechanisms and self-regulates A2 receptors on injured astrocytes. Since oxidative stress is the precipitating event, the corollary to this hypothesis is that in neurons, oxidative stress converges on PI3K/ERK to regulate the activity of BCL proteins that promote mitochondrial fusion and stabilization of the cell. Additional neuronal protection is achieved via A1-mediated activation of AKT with blockage of pro-death Bcl proteins and activation of survival Bcl-proteins. Conversely, in astrocytes, activation of the A2 receptor exacerbates loss of calcium control, swelling and cell death. This hypothesis for the role of astrocytes in the protection of neurons from oxidative stress-induced cell death will be tested by addressing the following specific questions. AIM 1: Can adenosine released by astrocytes silence neurons and protect them from the effects of exposure to 1,3-DNB? Aim 2: Does A1 receptor mediated signaling through PI3K, AKT and/or ERK block death- related members of the Bcl-family of proteins in neurons? Aim 3: Is the course of mitochondrial fusion or fission determined by or dependent upon binding of Mfn1/2, Bax/Bad/Bcl-XL and Drp 1? Aim 4: Does binding of proteins that alter mitochondrial morphology also alter membrane potential and function? Dinitrobenzene (DNB) provides and excellent model of energy deprivation syndromes with selective damage to astrocytes. This experimental approach will enable dissection of the role of BCL-proteins, mitofusins and Drp-1 in coordinating the loss of mitochondrial function and may provide new insights into neuronal/glial interactions that form the foundation for pathoclisis, or selective cellular susceptibility to environmental neurotoxicants. PUBLIC HEALTH RELEVANCE Astrocytes are supporting cells in the central nervous system. Data from our laboratories show that they are a primary target of many environmental chemicals that result in dysfunction of the central nervous system. As injury to the astrocyte progresses, ATP is converted to adenosine and is released into the extracellular space where it can interact with A1 receptors on neurons (protective) and A2 receptors on astrocytes (injurious). We propose here that in the acute phases of CNS injury, loss of neuronal function (silencing) is elicited by adenosine and may spare the neuron from the deleterious effects of oxidative stress and excitotoxicity.

描述（由申请人提供）：星形胶质细胞是神经细胞的重要组成部分，其功能障碍与多种特发性和遗传性疾病有关，包括阿尔茨海默病和帕金森病，以及能量剥夺综合征，如硫胺素缺乏症和抗代谢物中毒。健康的星形胶质细胞-神经元相互作用的主流模型是相邻膜之间持续而密切的物理接触，促进神经元的内稳态。虽然神经细胞中星形胶质细胞的损失通常被认为是一个负面事件，但我们在这里提出，在中毒的急性阶段，星形胶质细胞的损失可能保护神经元免受腺苷释放介导的进一步损伤。具体来说，我们假设dnb诱导的星形胶质细胞氧化应激诱导腺苷的释放，腺苷通过旁分泌机制激活神经元中的A1受体，并自我调节受损星形胶质细胞上的A2受体。由于氧化应激是沉淀事件，该假设的推论是，在神经元中，氧化应激聚集在PI3K/ERK上，调节BCL蛋白的活性，促进线粒体融合和细胞稳定。额外的神经元保护是通过a1介导的AKT激活，阻断促死亡Bcl蛋白和激活存活Bcl蛋白实现的。相反，在星形胶质细胞中，A2受体的激活加剧了钙控制的丧失、肿胀和细胞死亡。星形胶质细胞在保护神经元免受氧化应激诱导的细胞死亡中的作用的假设将通过解决以下具体问题来验证。AIM 1：星形胶质细胞释放的腺苷能使神经元沉默并保护它们免受1,3- dnb的影响吗？目的2：通过PI3K、AKT和/或ERK的A1受体介导的信号传导能否阻断神经元中与死亡相关的bcl蛋白家族成员？目的3：线粒体融合或裂变的过程是否由Mfn1/2、Bax/Bad/Bcl-XL和drp1的结合决定或依赖？目标4：改变线粒体形态的蛋白质结合是否也会改变膜电位和功能？二硝基苯（DNB）提供了能量剥夺综合征选择性损伤星形胶质细胞的良好模型。这种实验方法将使bcl蛋白、有丝分裂蛋白和Drp-1在协调线粒体功能丧失中的作用得以解剖，并可能为形成发病基础的神经元/胶质相互作用或对环境神经毒物的选择性细胞易感性提供新的见解。星形胶质细胞是中枢神经系统中的支持细胞。我们实验室的数据表明，它们是许多环境化学物质的主要目标，这些化学物质会导致中枢神经系统功能障碍。随着星形胶质细胞损伤的进展，ATP转化为腺苷并释放到细胞外空间，在那里它可以与神经元上的A1受体（保护性）和星形胶质细胞上的A2受体（损伤性）相互作用。我们在此提出，在中枢神经系统损伤的急性期，腺苷引起神经元功能丧失（沉默），并可能使神经元免受氧化应激和兴奋性毒性的有害影响。