Regulation of enteric motor neurocircuits by enteric glia in health and disease

健康和疾病中肠神经胶质细胞对肠运动神经回路的调节

• 批准号: 10655586
• 负责人: BRIAN D. GULBRANSEN
• 金额: $ 34.46万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10655586
• 关键词: Acute; Address; Affect; Biological Assay; Cells; Chronic; Colitis; Complex; Cues; Data; Development; Disease; Enteral; Enteric Nervous System; Feedback; Functional disorder; Funding; Gastrointestinal Diseases; Gastrointestinal Motility; Genetic; Glial Fibrillary Acidic Protein; Goals; Health; Human; Image; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Intestinal Motility; Intestinal Pseudo-Obstruction; Intestines; Irritable Bowel Syndrome; Knockout Mice; Mediator; Modeling; Motor; Motor Pathways; Mus; Muscle; Mutant Strains Mice; Neural Pathways; Neuroglia; Neuronal Plasticity; Neurons; Neurotransmitters; Nitrergic Neurons; Peristalsis; Pharmaceutical Preparations; Phase; Recruitment Activity; Reflex action; Regulation; Role; Signal Transduction; Specificity; Synapses; System; Testing; Tissues; Transgenic Mice; calcium indicator; cell motility; excitatory neuron; experimental study; gastrointestinal; glial activation; inhibitory neuron; insight; motility disorder; motor behavior; mouse model; neural circuit; neural network; neuroinflammation; neuron loss; neuronal excitability; neuronal survival; neuroregulation; neurotransmission; novel; novel strategies; novel therapeutics; recruit; therapeutic development

PROJECT SUMMARY Reflexive motor behaviors of the intestine including peristalsis are controlled by the enteric nervous system (ENS); a complex neural network embedded in the gut wall. Perturbations within the ENS contribute to the development of dysmotility in irritable bowel syndrome, inflammatory bowel disease, and severe motility disorders such as chronic intestinal pseudo-obstruction, but the mechanisms responsible for persistent changes in enteric neural circuitry are unknown. Recent data show that enteric glia, non-neuronal cells that surround enteric neurons, regulate neuronal excitability and contribute to neuroinflammation. The overall goal of this proposal is to define how specialized interactions between enteric glia and neurons regulate motility and how alterations in those mechanisms contribute to disease. This proposal tests the central hypothesis that enteric glia are specialized to potentiate the activity of ascending excitatory neural pathways involved in normal contractile motility, and that disruption of this regulatory system by inflammation contributes to neuronal hyperexcitability. This dual hypothesis will be tested in two specific aims that utilize genetically encoded calcium indicators to study neuron-glia interactions, glial chemogenetic actuators to study how glia modulate specific types of enteric neurons, and a post-inflammatory model of enteric neuroplasticity to study how glia contribute to neuronal hyperexcitability following inflammation. Aim 1 will test the hypothesis that enteric glia are specialized to sense excitatory neurons and potentiate ascending neural pathways involved in the contractile phase of motility. Aim 1.1 will use genetically encoded calcium indicators to study glial recruitment by polarized neural pathways in motility reflexes. Aim 1.2 will combine the chemogenetic activation of enteric glia with neuronal and glial imaging using genetically encoded calcium indicators to test the hypothesis that glia differentially affect subsets of enteric neurons. Aim 2 will test the hypothesis that glia contribute to neuronal hyperexcitability following colitis by increasing positive feedback to excitatory neurons and by reducing inhibitory feedback from inhibitory neurons. Aim 2.1 will study how altered interactions between glia and excitatory neurons contribute to neuronal hyperexcitability following colitis. Aim 2.2 will use mutant mice and selective drugs to study how glia contribute to neuronal hyperexcitability through interactions with inhibitory neurons. The results of this study will provide novel insight into glial mechanisms that regulate the excitability of enteric neural circuits. A better understanding of the glial mechanisms that regulate motility will facilitate the development of therapeutics for dysmotility by revealing novel targets to modify gastrointestinal reflexes.

项目概要 肠道的反射性运动行为（包括蠕动）由肠神经系统控制 （ENS）；嵌入肠壁的复杂神经网络。 ENS 内的扰动有助于 肠易激综合征、炎症性肠病和严重肠动力障碍的发展 慢性假性肠梗阻等疾病，但造成持续性肠梗阻的机制 肠神经回路的变化尚不清楚。最近的数据表明，肠胶质细胞、非神经元细胞 围绕肠神经元，调节神经元兴奋性并导致神经炎症。总体目标 该提案的目的是定义肠神经胶质细胞和神经元之间的专门相互作用如何调节运动和 这些机制的改变如何导致疾病。该提议检验了中心假设： 肠神经胶质细胞专门增强参与正常活动的上行兴奋性神经通路的活性 收缩运动，并且炎症对该调节系统的破坏有助于神经元 过度兴奋。这种双重假设将在利用基因编码的两个特定目标中进行测试 钙指示剂用于研究神经元-神经胶质细胞相互作用，神经胶质化学遗传学致动器用于研究神经胶质细胞如何调节 特定类型的肠神经元，以及肠神经可塑性的炎症后模型，以研究神经胶质细胞如何 导致炎症后神经元过度兴奋。目标 1 将检验肠神经胶质细胞的假设 专门用于感知兴奋性神经元并增强参与 运动的收缩期。目标 1.1 将使用基因编码的钙指标来研究神经胶质细胞的招募 通过运动反射中的极化神经通路。目标 1.2 将结合肠道的化学遗传学激活 使用基因编码的钙指示剂对神经胶质细胞进行神经元和神经胶质成像，以检验神经胶质细胞的假设 对肠神经元亚群有不同的影响。目标 2 将检验神经胶质细胞对神经元有贡献的假设 通过增加对兴奋性神经元的正反馈并减少结肠炎后的过度兴奋 来自抑制性神经元的抑制性反馈。目标 2.1 将研究如何改变神经胶质细胞和 兴奋性神经元导致结肠炎后神经元过度兴奋。目标 2.2 将使用突变小鼠 研究神经胶质细胞如何通过与抑制相互作用导致神经元过度兴奋的选择性药物 神经元。这项研究的结果将为调节兴奋性的神经胶质机制提供新的见解 肠神经回路。更好地了解调节运动的神经胶质机制将有助于 通过揭示改变胃肠道反射的新靶点来开发运动障碍疗法。

项目成果

LPAR1 regulates enteric nervous system function through glial signaling and contributes to chronic intestinal pseudo-obstruction.

LPAR1 通过神经胶质信号传导调节肠神经系统功能，并导致慢性假性肠梗阻。

• 发表时间: 2022-02-15
• 作者: Ahmadzai, Mohammad M;McClain, Jonathon L;Dharshika, Christine;Seguella, Luisa;Giancola, Fiorella;De Giorgio, Roberto;Gulbransen, Brian D
• 通讯作者: Gulbransen, Brian D

Cancer-induced morphological changes in enteric glial cells in the jejunum of Walker-256 tumor-bearing rats.

癌症诱导 Walker-256 荷瘤大鼠空肠肠胶质细胞形态变化。

• 发表时间: 2024-04
• 影响因子: 2.5
• 作者: Lima, Fabiana Galvão da Motta;Silva, Maysa Pacheco Alvarez da;Sestak, Sabrina Silva;Guarnier, Flávia Alessandra;de Oliveira, Ana Paula;Kuller, João Victor;Gulbransen, Brian David;Perles, Juliana Vanessa Colombo Martins;Zanoni, Jacqueline Nelisis
• 通讯作者: Zanoni, Jacqueline Nelisis

Stimulator of interferon genes (STING) expression in the enteric nervous system and contributions of glial STING in disease.

肠神经系统中干扰素基因 (STING) 表达的刺激物以及神经胶质 STING 在疾病中的贡献。

• 发表时间: 2023-07
• 影响因子: 3.5
• 作者: Dharshika, Christine;Gonzales, Jacques;Chow, Aaron;Morales;Gulbransen, Brian D
• 通讯作者: Gulbransen, Brian D

Enteric glia: the most alimentary of all glia.

肠神经胶质细胞：所有神经胶质细胞中最具营养性的。

• 发表时间: 2017-01-15
• 作者: Grubišić, Vladimir;Gulbransen, Brian D
• 通讯作者: Gulbransen, Brian D

Generation and characterization of polyclonal and monoclonal antibodies to human NTPDase2 including a blocking antibody.

人 NTPDase2 多克隆和单克隆抗体（包括封闭抗体）的生成和表征。

• 发表时间: 2017-09
• 影响因子: 3.5
• 作者: Pelletier, Julie;Agonsanou, Hervé;Delvalle, Ninotchska;Fausther, Michel;Salem, Mabrouka;Gulbransen, Brian;Sévigny, Jean
• 通讯作者: Sévigny, Jean