Human enteric glia: A novel target for motility and postoperative ileus

肠神经胶质细胞（EGCs）调节肠内稳态，并可能参与嘌呤能信号传导， 运动，但其确切作用尚不清楚，特别是在人类中。在发炎的状态下，它们转化为 “反应性更强的表型”，释放可能导致病理生理学的炎症介质。 问题：人EGCs（hEGCs）在胃肠道生理学和病理生理学中的作用不是 已知的，并解决这一关键的知识差距是重要的，在确定如何hEGCs调节GI 在健康和疾病中发挥作用。我们的初步数据支持hEGCs中的嘌呤能信号 调节细胞通讯、突触生理学、运动行为和炎症信号。意义 这些翻译研究的重点是神经胶质反应，机制， 并且在人ENS中神经胶质细胞与神经元的比率高7倍（与小鼠相比）。开创性的-机械的， 建议对“机械敏感性”、“运动调节”和术后肠梗阻进行转化研究。它 有必要开发和应用复杂的新技术来研究，即机械刺激 （压力、剪切应力、径向拉伸）、电流、Vm、Ca 2+波，使用 “嗅探细胞”，运动性的时空成像，和基因表达（即RiboTag小鼠和107-定制 “反应性神经胶质”的基因读出）。外科创伤/肠道操作、IL 1 β或条件培养基的研究 为研究人类肠道中的“反应性神经胶质”提供了精确的方法。总体假设：“人类 EGC是机械敏感性、细胞间通讯、突触生理学 人肠道中的神经肌肉传递和运动，炎症破坏了它们的 正常活动。嘌呤能信号在“功能和功能障碍”中起着关键作用。EGCs发挥 神经网络活动的抑制性调节。EGCs可能会发挥不同的（相反的）影响， 两个肌肉层通过在ENS中起作用来调节 蠕动反射和协调或同步运动。神经胶质活化破坏了 术后肠梗阻研究得到了一个有合作记录的研究者梦之队的支持， 极好的环境，强有力的初步数据（图1-16），“炎症性肠病”中的2篇新出版物 在2016年和一个修订出版物'GLIA'上的'基本hEGC模型'。我们的整体假设在4中得到验证 原始目的目的1：探讨人表皮细胞ATP释放的机械传导途径。目标2： 评估机械感觉转导和神经胶质通讯在ENS的完整的神经丛网络， 人体肠道目的3：探讨人表皮样细胞在运动调节中的作用。目标4：确定 术后肠梗阻炎症对反应性胶质细胞和运动性的影响，并在一定程度上使用人体组织， 是可能.影响：转化研究将填补神经胶质细胞在“小大脑”的知识的关键空白。 健康和疾病中的人类肠道，以及对动力障碍、肠道炎症和治疗的影响。

Enteric glial cells (EGCs) regulate intestinal homeostasis and may be involved in purinergic signaling and motility, but their precise role is not understood, especially in humans. In the inflamed state, they convert to a `more reactive phenotype', releasing inflammatory mediators that could contribute to pathophysiology. PROBLEM: The role of human EGCs (hEGCs) in the physiology and pathophysiology of the GI tract is not known, and addressing this critical gap in knowledge is important in determining how hEGCs modulate GI functions in health and disease. Our preliminary data support the concept that purinergic signals in hEGCs regulate cellular communication, synaptic physiology, motor behavior, and inflammatory signals. Significance of these translational studies is underscored by significant species differences in glial responses, mechanisms and a 7 fold higher glial to neuron ratio in human ENS (versus mouse). Groundbreaking – mechanistic, translational studies are proposed on `mechanosensitivity', `modulation of motility' and postoperative ileus. It became necessary to develop and apply sophisticated new technologies to study i.e. mechanical stimulation (pressure, shear stress, radial stretch) of hEGCs, currents, Vm, Ca2+waves, monitor ATP release using a `sniffer cell', spaciotemporal imaging of motility, and gene expression (i.e. RiboTag mouse & a 107-custom gene readout of `reactive glia'). Studies on surgical trauma/intestinal manipulation, IL1β or conditioned media from hEGCs provide precise ways to study `reactive glia' in human gut. OVERALL HYPOTHESIS: “Human EGCs are critical regulators of mechanosensitivity, cell-to-cell communication, synaptic physiology, neuromuscular transmission and motility in the human intestinal tract and inflammation disrupts their normal activity. Purinergic signaling plays a pivotal role in `function and dysfunction'. EGCs exert inhibitory modulation of neural network activity. EGCs may exert differential (opposing) effects in the two muscle layers by acting in the ENS to modulate ascending and descending phases of the peristaltic reflex and coordinate or synchronize motility. Glial activation disrupts motility in postoperative ileus. Studies are supported by a dream team of investigators with a record of collaboration, a superb environment, strong preliminary data (Figs 1-16), 2 new publications in `Inflammatory Bowel Diseases' in 2016 and one revised publication to `GLIA' on the `basic hEGC model'. Our overall hypothesis is tested in 4 original Aims. AIM 1: To investigate mechanotransduction pathways of ATP release in hEGCs. AIM 2: To evaluate mechanosensory transduction and glial communication in the ENS of intact neural plexus networks in human intestine. AIM 3: To determine the role of hEGCs in the modulation of motility. AIM 4: To determine the impact of inflammation in postoperative ileus on reactive glia and motility and use human tissue to the extent it is possible. IMPACT: Translational studies will fill a critical gap in knowledge of glia in the `little brain' of the human gut in health and disease, with implications for motility disorders, gut inflammation and therapeutics.