Glial Cells and Polyamine Signaling in the Central Nervous System

中枢神经系统中的胶质细胞和多胺信号传导

• 批准号: 10351492
• 负责人: SERGUEI N SKATCHKOV
• 金额: $ 15.47万
• 依托单位: UNIVERSIDAD CENTRAL DEL CARIBE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10351492
• 关键词: Address; Adult; Aging; Alzheimer' s Disease; Animal Model; Astrocytes; Attention; Brain; Brain Diseases; Brain Injuries; Central Nervous System Diseases; Connexin 43; Development; Diagnosis; Disease; Elements; Epilepsy; Foundations; Future; Gap Junctions; Giant Cells; HIV-associated neurocognitive disorder; Human; Huntington Disease; Ischemia; Knowledge; Longevity; Measures; Metabolic Diseases; Morbidity - disease rate; Nerve Degeneration; Neuraxis; Neuroglia; Neurons; Parkinson Disease; Pathologic; Pathology; Pathway interactions; Physiological; Physiology; Polyamines; Prevention; Process; Public Health; Publications; Research; Retina; Risk; Role; SeSAME syndrome; Signal Transduction; Slice; Source; Spermidine; Spermine; Syndrome; Techniques; Testing; Therapeutic; Transgenic Animals; Trauma; Work; extracellular; graduate student; mortality; neglect; neurocognitive disorder; neuroprotection; neurotoxicity; novel; parent grant; uptake

Project Summary/Abstract (from Parent grant): Emerging recent publications show that polyamines (PAs) are key players in the exceedingly common disorders of aging and HIV associated neurocognitive disorders (HAND), Alzheimer's, Huntington's and Parkinson diseases as well as in Snyder-Robinson and SeSAME/EAST syndromes. PAs are released in whole brain from unknown sources during neuronal activity and trauma. PAs demonstrate neuroprotection against neurotoxicity, ischemia, brain injury and also increase longevity. Since PA content declines with aging or during pathology, the neuroprotection afforded by PAs can decline as well. This substantially increases the risk of morbidity and mortality. Despite its public health importance, relatively little is known about PA fluxes in brain and insufficient attention is paid to glial cells in CNS. Intriguingly, we found that in healthy adult brain and retina, glial cells but not neurons accumulate preferentially PAs such as spermidine (SD) and spermine (SP). We further recently found that PAs are the major openers of astrocytic connexin-43 (Cx43) gap junctions (GJs). Therefore, since Cx43 GJs are the major communicating channels between astrocytes, PAs keep glial syncytium integrity that may help to hold healthy brain status, however in many (patho)physiological conditions the situations are not well studied. The storage of internal PAs and their effects regulated by glia on brain function are some of the remaining mysteries and our findings raise key questions: (i) What are the mechanisms that underlie such uneven distribution and accumulation of PAs between astrocytes and neurons? (ii) What are the mechanisms of PA release in CNS from glia? (iii) What are the consequences of PA fluxes within the brain on neuronal function? and (iv) Ultimately, what are the roles of PAs in brain disorders and diseases? The glial PA pathways hitherto have been neglected, although it is evident that these molecules are key elements for normal brain status and their metabolic disorders, apparently, cause the development of many pathological syndromes and diseases. We have developed techniques for measuring PA fluxes in brain slices and retina and will use transgenic animal models of HAND (and in the future of other diseases) to study (patho)physiology of PA translocation. In this project, we will test the original hypothesis that PAs are novel “gliotransmitters” that (i) are transported into glia, (ii) open astrocytic intercellular gap junctions, (iii) propagate in the astrocyte-to-astrocyte syncytium (AIM-1) and (iv) are released from glia upon local stimulation (v) to regulate the neuronal-glial network (AIM-2). We will address these two aims to determine mechanisms of PA uptake/accumulation/release/signaling in CNS. The studies will lead to new scientific knowledge and research opportunities for graduate students to further understand neurodegenerative processes, helping advance diagnosis, treatment and prevention.

项目摘要/摘要（来自父母赠款）： 新兴的最近出版物表明，多胺（PAS）是极为常见的主要参与者 衰老和艾滋病毒相关的神经认知疾病（手），阿尔茨海默氏症，亨廷顿和 帕金森疾病以及Snyder-Robinson和芝麻/东综合症。 pas全部发布 神经元活性和创伤期间未知来源的大脑。 PAS展示了针对的神经保护 神经毒性，缺血，脑损伤以及增加寿命。因为PA的内容随着衰老或期间而下降 病理学，PA所提供的神经保护也会下降。这大大增加了 发病率和死亡率。尽管公共健康的重要性，但对大脑中的PA通量知之甚少 并且对中枢神经系统的神经胶质细胞不足。 有趣的是，我们发现在健康的成年大脑和视网膜中，神经胶质细胞而不是神经元积累 优先使用PAS，例如精子（SD）和精子（SP）。我们最近进一步发现PA是 星形胶质细胞连接蛋白43（CX43）间隙连接（GJS）的主要开瓶器。因此，由于CX43 GJ是主要的 在星形胶质细胞之间进行通道，PAS保持神经胶质合成的完整性，这可能有助于保持健康 然而，在许多（病原）生理状况下，情况并不是很好。 内部PA的存储及其受神经胶质调节对脑功能调节的影响是一些 剩下的谜团和我们的发现提出了关键问题：（i）这种机制是什么基础 星形胶质细胞和神经元之间PA的分布不均和积累？ （ii）有什么机制 来自GLIA中枢神经系统的PA释放？ （iii）大脑内PA通量在神经元内的后果是什么 功能？ （iv）最终，PA在脑疾病和疾病中的作用是什么？ 迄今已忽略了神经胶质PA途径，尽管有证据表明这些分子是关键 正常大脑状况及其代谢疾病的元素显然导致许多 病理综合征和疾病。我们开发了用于测量脑切片中PA通量的技术 和视网膜，并将使用手的转基因动物模型（以及其他疾病的未来）来研究 （病原）PA易位的生理学。在这个项目中，我们将测试原始假设，即PA是新颖的 （i）被转运到神经胶质的“ Gliotransmitters”，（ii）开放的星形细胞间间隙连接，（iii） 在局部刺激后，在星形胶质细胞到胃细胞合成（AIM-1）和（iv）中传播。 （v）调节神经元网络（AIM-2）。 我们将解决这两个目的，以确定PA吸收/累积/释放/信号的机制 CNS。这些研究将为研究生带来新的科学知识和研究机会 进一步了解神经退行性过程，有助于提高诊断，治疗和预防。