Role of enteric glia in the death of neurons during gut inflammation

肠神经胶质细胞在肠道炎症期间神经元死亡中的作用

基本信息

  • 批准号:
    9269069
  • 负责人:
  • 金额:
    $ 42.41万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2015
  • 资助国家:
    美国
  • 起止时间:
    2015-07-15 至 2020-04-30
  • 项目状态:
    已结题

项目摘要

 DESCRIPTION (provided by applicant): Reflex behaviors of the intestine including peristalsis are orchestrated by the enteric nervous system (ENS); a complex neural network embedded in the gut wall. Inflammation profoundly alters ENS circuits controlling motility by promoting enteric ganglionitis; an inflammatory neuropathy characterized by the death of enteric neurons. Neuropathy is increasingly recognized as a trigger for persistent gut dysfunction in gastrointestinal (GI) motility and functional bowel disorders but the mechanisms that regulate neuropathy are not understood. This proposal investigates the role of enteric glial cells, astrocyte-like cells that surround neurons in the ENS, in the regulation of enteric neuropathy. The proposed studies will use in vivo models of GI inflammation, transgenic mice, immunohistochemistry, live-cell imaging with fluorescent probes, biosensing assays and functional tests to study neuron-glia interactions. The central hypothesis is that purinergic activation of enteric glial cells differentially regulates neuron survival depending on glial activation by ADP or adenosine. There are 2 specific aims in this proposal, each with three sub-aims. Each aim will link in vitro mechanistic studies in tissue from humans and mice with in vivo functional studies in transgenic mice. Aim 1 will test the hypothesis that glial Ca2+ responses driven by ADP cause reactive gliosis, neuron death and gut dysfunction. Specific aim 1A will test how activation of glial Ca2+ responses in GFAP:hM3Dq mice or human tissue transduced with glial- specific vectors affects the induction of reactive gliosis and neuron death. Aim 1B wil test whether glial cells directly drive neuron death by releasing neurotoxic substances or if glial driven neuron death requires immune cell recruitment. Mice with an inducible ablation of connexin-43 or MHC-II in glia will be used to specifically interfere with gliotransmitter release o immune cell recruitment, respectively. Aim 1C will test how manipulation of gliosis using the transgenic mice listed above affects in vivo and ex vivo intestinal function. Aim 2 will test the hypothesis that adenosine inhibits reactive gliosis and stimulates protective mechanisms in glia to preserve ENS function. Aim 2A will use drugs and CD73 null mice to test if activation of glial adenosine receptors is necessary and/or sufficient to reverse reactive gliosis. Aim 2B will test whether the neuroprotective actions of glial A2BR activation are mediated by altering the release of glial mediators or by decreasing the inflammatory infiltrate following in vivo inflammation in CD73 null mice. Aim 2C will use in vivo inflammation, drugs and CD73 null mice to determine how manipulation of glial adenosine signaling impacts in vivo and ex vivo assays of gut function following acute inflammation. Significance: Intestinal inflammation can drive enteric neuropathy, leading to persistent gut dysfunction in GI motility disorders. Understanding how glial mechanisms both promote, and limit enteric neuropathies is important because it could lead to the discovery of novel therapeutic targets and a common causative mechanism of neuron death in GI motility disorders, functional bowel disorders and inflammatory bowel disease.
 描述(由申请人提供):肠的反射行为(包括痉挛)由肠神经系统(ENS)协调; ENS是一种嵌入肠壁的复杂神经网络。炎症通过促进肠蠕动而深刻地改变了控制运动的ENS回路 神经节炎;一种以肠神经元死亡为特征的炎性神经病。神经病变越来越多地被认为是胃肠道(GI)运动和功能性肠病中持续性肠道功能障碍的触发因素,但调节神经病变的机制尚不清楚。该建议调查肠神经胶质细胞,星形胶质细胞样细胞,神经元周围的ENS,在肠道神经病变的调节中的作用。拟议的研究将使用胃肠道炎症的体内模型、转基因小鼠、免疫组织化学、荧光探针活细胞成像、生物传感测定和功能测试来研究神经元-胶质细胞相互作用。核心假设是肠神经胶质细胞的嘌呤能激活差异调节神经元的存活取决于ADP或腺苷激活的神经胶质细胞。本提案有两个具体目标,每个目标有三个次级目标。每个目标都将把人类和小鼠组织的体外机制研究与转基因小鼠的体内功能研究联系起来。目的1将验证由ADP驱动的胶质细胞Ca 2+反应导致反应性胶质细胞增生、神经元死亡和肠道功能障碍的假设。具体目标1A将测试用胶质细胞特异性载体转导的GFAP:hM 3Dq小鼠或人组织中胶质细胞Ca 2+应答的激活如何影响反应性胶质增生和神经元死亡的诱导。目的1B将测试胶质细胞是否通过释放神经毒性物质直接驱动神经元死亡,或者胶质细胞是否通过释放神经毒性物质直接驱动神经元死亡。 驱动的神经元死亡需要免疫细胞募集。具有神经胶质中连接蛋白-43或MHC-II的诱导性消融的小鼠将分别用于特异性干扰神经胶质递质释放或免疫细胞募集。目的1C将测试使用上面列出的转基因小鼠操纵胶质增生如何影响体内和离体肠功能。目的2将验证腺苷抑制反应性胶质增生并刺激胶质细胞保护机制以保护ENS功能的假设。目标2A将使用药物和CD 73缺失小鼠来测试胶质腺苷受体的激活是否是逆转反应性胶质增生所必需的和/或足够的。目的2B将测试胶质A2 BR活化的神经保护作用是否通过改变胶质介质的释放或通过减少CD 73敲除小鼠体内炎症后的炎性浸润来介导。目的2C将使用体内炎症、药物和CD 73缺失小鼠来确定神经胶质腺苷信号传导的操纵如何影响急性炎症后肠道功能的体内和离体测定。意义:肠道炎症可驱动肠神经病变,导致GI动力障碍的持续性肠道功能障碍。了解神经胶质机制如何促进和限制肠道神经病变是很重要的,因为它可能导致发现新的治疗靶点和神经元死亡的常见致病机制,在胃肠道动力障碍,功能性肠病和炎症性肠病。

项目成果

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BRIAN D. GULBRANSEN其他文献

BRIAN D. GULBRANSEN的其他文献

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{{ truncateString('BRIAN D. GULBRANSEN', 18)}}的其他基金

Neurohumoral regulation of PVAT
PVAT 的神经体液调节
  • 批准号:
    10543522
  • 财政年份:
    2021
  • 资助金额:
    $ 42.41万
  • 项目类别:
Neurohumoral regulation of PVAT
PVAT 的神经体液调节
  • 批准号:
    10331579
  • 财政年份:
    2021
  • 资助金额:
    $ 42.41万
  • 项目类别:
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:
    10213012
  • 财政年份:
    2019
  • 资助金额:
    $ 42.41万
  • 项目类别:
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:
    10436828
  • 财政年份:
    2019
  • 资助金额:
    $ 42.41万
  • 项目类别:
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
  • 财政年份:
    2019
  • 资助金额:
    $ 42.41万
  • 项目类别:
Enteric glia and visceral pain
肠神经胶质细胞和内脏疼痛
  • 批准号:
    10361567
  • 财政年份:
    2019
  • 资助金额:
    $ 42.41万
  • 项目类别:
Enteric glia and visceral pain
肠神经胶质细胞和内脏疼痛
  • 批准号:
    10112902
  • 财政年份:
    2019
  • 资助金额:
    $ 42.41万
  • 项目类别:

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