Polyamines and Brain Signaling

多胺和大脑信号传导

• 批准号: 7985116
• 负责人: SERGUEI N SKATCHKOV
• 金额: $ 31.57万
• 依托单位: UNIVERSIDAD CENTRAL DEL CARIBE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7985116
• 关键词: Address; Adult; Anticoagulants; Antidepressive Agents; Antioxidants; Astrocytes; Attention; Biosensor; Blood Vessels; Brain; Brain Injuries; Buffers; Cerebrospinal Fluid; Cessation of life; Connexins; Data; Employee Strikes; Environment; Enzymes; Epilepsy; Future; Gap Junctions; Genetic; Giant Cells; Glutamates; Interneurons; Ischemia; Lead; Longevity; Membrane; Monitor; Neuroglia; Neurons; Organic Cation Transporter; Ornithine Decarboxylase; Pathway interactions; Physiological; Polyamines; Potassium; Putrescine; Pyramidal Cells; Reporting; Retina; Role; Signal Transduction; Signaling Molecule; Source; Spermidine; Spermidine Synthase; Spermine; Stroke; Testing; Therapeutic; Transferase; Trauma; Work; dietary supplements; excitotoxicity; extracellular; falls; insight; neuroprotection; neurotoxicity; novel; public health relevance; receptor; spreading depression; uptake

DESCRIPTION (provided by applicant): The polyamines (PA), spermine (SPM) and spermidine (SPD), are reported to be neuroprotective and increase longevity. They are released in whole brain from unknown sources during neuronal activity and trauma. Our preliminary data indicate that endogenous SPM and SPD are predominantly stored in glial cells in brain and retina, not in neurons, but the enzymes that synthesize SPM and SPD are lacking in glial cells. We also find many conditions under which glia release PA. These findings lead us to the working hypothesis that SPM/SPD are novel glio-modulators released from and buffered within the glial syncytium. Neuronal excitation results in a fall of [Na+]o, [Ca2+]o and [H+]o together with increased [K+]o, providing conditions that facilitate opening of hemichannels in glia and release of SPM from glia to the neuronal environment. Increased extracellular SPM can then modulate neuronal receptors and channels. In this proposal we specifically ask: (i) what is the mechanism of SPM permeation and accumulation in glia, (ii) how is release of SPM regulated and (iii) what are the functional consequences of SPM bidirectional flux through the glial membrane? These questions will be addressed by examining mechanisms of SPM transport and the effects of SPM in the glial-neuronal network. Using a novel SPM-biosensor we will monitor extracellular SPM concentration changes during trauma and normal conditions. These studies will elucidate the roles of SPM as an extracellular signaling molecule between glia and neurons in physiological and pathological situations. The results will provide important information for future efforts to understand and minimize neuronal damage during stroke and ischemia. PUBLIC HEALTH RELEVANCE: Project Narrative In this project we will determine the mechanisms of the polyamines spermine (SPM) and spermidine (SPD) accumulation in and release from glia and their role in the neuronal network. These studies will elucidate the roles of SPM/SPD as extracellular signaling molecules between glia and neurons in physiological and pathological conditions. The results will provide important information for future efforts to understand and minimize neuronal damage during K+-spreading depression, stroke, ischemia and epilepsy in the brain.

描述（由申请人提供）： 据报道，多胺（PA）、精胺（SPM）和亚精胺（SPD）具有神经保护作用并延长寿命。它们在神经元活动和创伤期间从未知来源释放到整个大脑中。我们的初步数据表明，内源性SPM和SPD主要储存在脑和视网膜的神经胶质细胞中，而不是在神经元中，但合成SPM和SPD的酶在神经胶质细胞中缺乏。我们还发现了许多条件下，胶质细胞释放PA。这些发现使我们的工作假设，SPM/SPD是新的神经胶质细胞调节剂释放和缓冲内的神经胶质细胞合胞体。神经元兴奋导致[Na+]o、[Ca 2 +]o和[H+]o的下降以及[K+]o的增加，提供了促进神经胶质中半通道开放和SPM从神经胶质释放到神经元环境的条件。细胞外SPM的增加可以调节神经元受体和通道。在这个建议中，我们具体问：（一）什么是SPM渗透和积累在神经胶质细胞的机制，（二）如何释放SPM调节和（三）什么是SPM双向通量通过神经胶质细胞膜的功能后果？这些问题将通过研究SPM运输机制和SPM在神经胶质-神经元网络中的作用来解决。使用一种新的SPM生物传感器，我们将监测在创伤和正常条件下细胞外SPM浓度的变化。这些研究将阐明SPM作为神经胶质细胞和神经元之间的细胞外信号分子在生理和病理情况下的作用。这些结果将为未来了解和减少中风和缺血期间的神经元损伤提供重要信息。 公共卫生关系： 在这个项目中，我们将确定多胺精胺（SPM）和亚精胺（SPD）在神经胶质细胞中积累和释放的机制及其在神经网络中的作用。这些研究将阐明SPM/SPD作为神经胶质细胞和神经元之间的细胞外信号分子在生理和病理条件下的作用。这些结果将为未来的努力提供重要的信息，以了解和尽量减少K+扩散抑制，中风，缺血和癫痫在大脑中的神经元损伤。