Polyamines and Brain Signaling

多胺和大脑信号传导

• 批准号: 8117115
• 负责人: SERGUEI N SKATCHKOV
• 金额: $ 30.94万
• 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/8117115
• 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），精子（SPM）和精子（SPD）是神经保护性的，并增加了寿命。它们在神经元活动和创伤期间从未知来源中释放出来。我们的初步数据表明，内源性SPM和SPD主要存储在脑和视网膜中的神经胶质细胞中，而不是神经元中，而是合成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，在哪些条件下释放PA。这些发现使我们提出了这样的假设，即SPM/SPD是从神经胶质合成中释放并缓冲的新型胶质调节剂。神经元激发导致[Na+] O，[Ca2+] O和[H+] O以及[K+] O的增加，提供了促进胶质中的半通道和SPM从GliA释放到神经元环境的条件。细胞外SPM随后可以调节神经元受体和通道。在此提案中，我们特别提出：（i）SPM渗透和胶质中积累的机理是什么，（ii）SPM调节的释放是如何通过神经胶质膜的SPM双向通量的功能后果是什么？这些问题将通过检查SPM传输的机制以及SPM在神经神经元网络中的影响。使用新型的SPM生物传感器，我们将在创伤和正常情况下监测细胞外SPM浓度变化。这些研究将阐明SPM作为生理和病理状况中神经元之间的细胞外信号分子的作用。结果将为未来的努力提供重要信息，以了解和最大程度地减少中风和缺血期间神经元损害。 公共卫生相关性： 该项目中的项目叙述我们将确定多胺精子（SPM）和精子（SPD）在GLIA中的积累和释放的机理及其在神经元网络中的作用。这些研究将阐明SPM/SPD作为生理和病理条件下神经元之间细胞外信号分子的作用。结果将为未来的努力提供重要的信息，以了解和最大程度地减少K+抑郁症，中风，缺血和大脑癫痫的神经元损害。