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Neuroinflammatory Regulation of Colonic Mechanosensory Activity

结肠机械感觉活动的神经炎症调节

基本信息

批准号：
10395490
负责人：
Liya Qiao
金额：
$ 34.93万
依托单位：
VIRGINIA COMMONWEALTH UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-01 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10395490
关键词：
Ablation Afferent Neurons Affinity Affinity Chromatography Animals Behavior assessment Brain-Derived Neurotrophic Factor Cells Clinical Colon Colony-Stimulating Factor Receptors Colony-Stimulating Factors Colorectal Disease Distal Female Fluorescence-Activated Cell Sorting Gender Genetic Goals Human Hypersensitivity Image Imaging Techniques Immune In Vitro Inflammatory Intestines Irritable Bowel Syndrome Knockout Mice Macrophage Colony-Stimulating Factor Measurement Measures Mechanics Mediating Mediation Mediator of activation protein Modeling Modification Mus Neuroglia Neurons Neurotrophic Tyrosine Kinase Receptor Type 2 Nociception Nociceptors Pain Patients Piezo 2 ion channel Production Protein Isoforms Prothrombin Regulation Ribosomes Role Sensory Spinal Ganglia System TNF gene Translating Triad Acrylic Resin base cell type colorectal distension conditional knockout cytokine design gastrointestinal in vivo insight macrophage male mechanotransduction neurochemistry neuroinflammation receptor response sex sexual dimorphism tool treatment strategy

项目摘要

PROJECT SUMMARY The enhanced colorectal mechanosensation in colonic hypersensitivity and gastrointestinal (GI) pain is initiated and mediated by primary afferent neurons in dorsal root ganglia (DRG), perhaps by Piezo2-mediated mechanotransduction in a subpopulation of colonic nociceptive afferent neurons. Macrophage colony- stimulating factor (CSF1) and brain-derived neurotrophic factor (BDNF) are two potent mediators in the genesis of mechanical pain, however, DRG nociceptive neurons do not express CSF1 receptor Csf1r and few neurons have BDNF receptor TrkB. Macrophages and glial cells including satellite glial cells (SGCs) express Csf1r and/or TrkB isoforms, therefore they are likely primary recipients of CSF1 and BDNF. In DRG, macrophages and glial cells surround sensory neurons to form a neuronal-glial-immune cell triad. Upon activation, macrophages and glial cells release a variety of inflammatory factors such as the pronociceptive cytokine tumor necrosis factor alpha (TNFα) that can act on nearby sensory neurons. In our preliminary study, macrophages and glial cells act differentially in producing TNFα in DRG of male and female mice in colonic hypersensitivity models. TNFα and CSF1-conditioned human macrophage culture medium activate a subset of Piezo2 expressing colonic afferent neurons. Macrophages are also activated by BDNF to produce TNFα. We postulate that macrophages and glial cells are activated by CSF1 and BDNF in DRG to generate TNFα that activates Piezo2 expressing colonic afferent neurons, leading to colonic mechanosensory sensitization. We will pursue three interrelated Specific Aims. In AIM 1, we will distinguish the roles of macrophages and glial cells in producing TNFα to generate neuroinflammation in DRG in male and female mice to regulate colonic hypersensitivity. We will implement genetic tools for conditional ablation/inhibition of macrophages or glial cells, and examine colorectal distension (CRD)-evoked mechanosensory activity by in vivo DRG imaging. In AIM 2, we will determine Piezo2 in DRG nociceptive neurons in mediation of neuroinflammatory regulation of colonic hypersensitivity. We will use our Piezo2 conditional knockout mouse line to perform direct neurochemical measurement and study the functional roles of Piezo2 in mediation of neuroinflammation (TNFα)-regulated colonic mechanosensory activity. In AIM 3, we will characterize the regulation of macrophages and glial cells by CSF1 and BDNF in male and female mice in producing TNFα to regulate Piezo2 expressing colonic afferent neurons. In many species and systems, the expression of TrkB receptors is sex-related. We will examine whether TrkB receptors are sexually dimorphic in macrophages and glial cells to interpret the distinct roles of macrophages and glial cells in colonic hypersensitivity in male and female mice, and suggest mechanism of gender-related GI pain in patients. Our studies using in vivo, in vitro, genetic tools, and imaging techniques in characterizing the impact of neuroinflammation on colonic mechanosensory activity will open new avenues in designing specific target(s) in the treatment of GI pain and functional bowel disorders.

项目总结增强的结直肠机械感觉治疗结肠过敏和胃肠道(GI)疼痛背根神经节初级传入神经元的启动和介导，可能是由Piezo2介导的结肠伤害性传入神经元亚群中的机械转导。巨噬细胞集落- 刺激因子(CSF1)和脑源性神经营养因子(BDNF)是两个强有力的介导物。机械痛的发生，但DRG伤害性神经元不表达CSF1受体CSF1R，而且很少神经元上有BDNF受体TrkB。巨噬细胞和胶质细胞，包括卫星胶质细胞(SGCs)表达 CSF1R和/或TrkB亚型，因此它们可能是CSF1和BDNF的主要受体。在DRG中，巨噬细胞和神经胶质细胞包围感觉神经元，形成神经元-神经胶质-免疫细胞三联体。vt.在.的基础上激活后，巨噬细胞和胶质细胞释放多种炎症因子，如前伤害性感受器细胞因子肿瘤坏死因子α可作用于附近的感觉神经元。在我们的初步研究中，巨噬细胞和神经胶质细胞在雄性和雌性小鼠结肠背根神经节产生肿瘤坏死因子α中的不同作用过敏症模型。肿瘤坏死因子α和CSF1条件人巨噬细胞培养液激活表达结肠传入神经元的Piezo2。巨噬细胞也被脑源性神经营养因子激活以产生肿瘤坏死因子α。我们假设巨噬细胞和胶质细胞被背根神经节中的CSF1和BDNF2激活而产生肿瘤坏死因子α，从而激活表达结肠传入神经元的Piezo2，导致结肠机械感觉敏化。我们会追求三个相互关联的具体目标。在AIM 1中，我们将区分巨噬细胞和神经胶质细胞在产生肿瘤坏死因子α在雄性和雌性小鼠背根神经节产生神经炎症以调节结肠过敏症。我们将实施有条件地消融/抑制巨噬细胞或胶质细胞的基因工具，并通过在体DRG成像检测结肠扩张(CRD)诱发的机械感觉活动。在目标2中，我们将测定DRG伤害性神经元中Piezo2在介导结肠神经炎性调节中的作用过敏症。我们将使用我们的Piezo2条件性基因敲除小鼠品系进行直接神经化学检测和研究Piezo2在α调节的神经炎症中的功能作用结肠机械感觉活动。在AIM 3中，我们将描述巨噬细胞和神经胶质细胞的调节雌雄小鼠产生肿瘤坏死因子α对Piezo2表达的影响神经元。在许多物种和系统中，TrkB受体的表达与性别有关。我们将研究 TrkB受体在巨噬细胞和神经胶质细胞中是否是性二态的，以解释其不同的作用巨噬细胞和胶质细胞在雄性和雌性小鼠结肠超敏反应中的作用患者中与性别相关的胃肠道疼痛。我们的研究使用了体内、体外、基因工具和成像技术表征神经炎症对结肠机械感觉活动的影响将开辟新的途径设计治疗胃肠道疼痛和功能性肠病的特异性靶点(S)。