Neuronal Contribution to the Propagation of Inflammation in the Central Nervous System

神经元对中枢神经系统炎症传播的贡献

• 批准号: 10042405
• 负责人: Erkin Seker
• 金额: $ 14.48万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10042405
• 关键词: Address; Anatomy; Apoptotic; Astrocytes; Axon; Axonal Transport; Biochemical; Blood Vessels; Brain; Brain region; Caregivers; Cell Culture Techniques; Cell Death; Chemicals; Collaborations; Complex; Degenerative Disorder; Diffusion; Disease; Distal; Distant; Electrodes; Electrophysiology (science); Engineering; Ensure; Exposure to; Fluorescence Microscopy; Foreign Bodies; Foundations; Future; Glutamates; Goals; Guanine Nucleotide Exchange Factors; Histologic; Hydrostatic Pressure; In Vitro; Inflammation; Inflammatory; Injury; Interferons; Lesion; Liquid substance; Malignant Neoplasms; Mediator of activation protein; Methodology; Microfluidics; Microglia; Modeling; Monitor; Nanotechnology; Neuraxis; Neurodegenerative Disorders; Neurologic; Neurons; Neurotransmitters; Patients; Phenotype; Pilot Projects; Play; Quality of life; Rattus; Resistance; Role; Route; Signal Transduction; Site; Slice; Source; Study models; TNF gene; Testing; Therapeutic; Tissues; Traumatic Brain Injury; astrogliosis; base; cell type; excitotoxicity; in vitro Model; in vivo; insight; miniaturize; nerve supply; neural implant; neuroinflammation; neurophysiology; neurotransmission; novel; painful neuropathy; prevent; relating to nervous system; response; spatial relationship; therapeutic evaluation; tissue culture; transmission process

Project Summary An intriguing phenomenon is observed in many neuroinflammation-based conditions, where neuroinflammatory responses and neurophysiological changes occur distant to a focal brain lesion. This contributes to the therapeutic challenges in managing neuroinflammatory diseases. Due to large diffusion distances, soluble factor-based signaling is unlikely to cause distal neuroinflammatory responses, while focal neuroinflammation is too specific to be explained by vascular transport of soluble factors. Our central hypothesis is that intra-axonal signaling and electrophysiological signals (e.g., excitotoxicity) contribute to the transmission of neuroinflammatory triggers from the site of insult to distal regions. Distinguishing the relative contributions of these complex factors in vivo, where many confounding signals exist, is extremely difficult if not impossible. However, conventional in vitro tissue culture models are also inadequate for addressing this problem because they do not recapitulate the spatial relationship of this phenomenon. In order to address this need, we will employ a microfluidic in vitro model that consist of two physically distinct culture chambers (e.g., source and target, corresponding to immediate and distal anatomical regions) interconnected by microchannels. This platform will allow for organotypic brain slice culture and the two chambers will be electrically connected by axonal projections routed through the microchannels, while the chambers will remain chemically separated by the high fluidic resistance of the channels and differential hydrostatic pressure at each chamber. Each transparent chamber and the microchannels will allow for monitoring histological and biochemical changes and each will contain multifunctional multiple electrode arrays for monitoring electrophysiological activity, allowing us to assess the relative contribution of intra-axonal signaling and electrophysiological signal to the propagation of neuroinflammation between discrete brain regions. Collectively, the pilot study is expected to (i) validate the propagation of neuroinflammation observed in vivo and (ii) establish the foundation for future mechanistic studies of neuroinflammation and its intra-axonal transmission with unprecedented control and detail.

项目摘要 在许多基于神经炎症的疾病中观察到一个有趣的现象，其中神经炎症 反应和神经生理学变化发生在远离局灶性脑损伤的地方。这有助于治疗 管理神经炎性疾病的挑战。由于大的扩散距离，基于可溶性因子的信号传导 不太可能引起远端神经炎性反应，而局灶性神经炎性反应太特异而无法解释 通过可溶性因子的血管运输。我们的中心假设是，轴突内信号和电生理 信号（例如，兴奋性毒性）有助于神经炎性触发物从损伤部位传递到 远端区域。区分这些复杂因素在体内的相对贡献，其中许多混杂因素 信号存在，是非常困难的，如果不是不可能的。然而，常规的体外组织培养模型也不适用。 这些数据不足以解决这一问题，因为它们没有概括这一现象的空间关系。 为了满足这一需求，我们将采用微流体体外模型，该模型由两个物理上不同的 培养室（例如，源和目标，对应于直接和远端解剖区域 通过微通道该平台将允许器官型脑切片培养，并且两个腔室将被电连接。 由轴突突起连接，通过微通道路由，而室将保持化学 由通道的高流体阻力和每个腔室的流体静压差隔开。每个 透明腔室和微通道将允许监测组织学和生物化学变化， 将包含多功能多电极阵列，用于监测电生理活动，使我们能够评估 轴突内信号和电生理信号对神经元传导的相对贡献 神经炎症。总的来说，试点研究预计将（i）验证 在体内观察到的神经炎症的传播和（ii）建立未来的机制研究的基础， 神经炎症及其轴突内传递具有前所未有的控制和细节。