Neuroimmune regulation of gut function

感知神经元对于检测胃肠道内的环境和内部刺激至关重要，这些刺激介导了对有害、炎症、代谢和微生物刺激的生理反应，如疼痛和饱腹感。除了沿肠-脑轴介导反射反应外，通过从传入终端释放信号分子介导的感觉传入的效应功能在形成与微生物组、免疫细胞、肠神经元和粘膜界面屏障功能的局部相互作用中起关键作用。我们最近对结肠神经元进行的单细胞RNAseq研究的数据，为不同感觉神经群中介质表达的多样性提供了以前未被认识的全面见解，并为肠内不同细胞群和信号通路的相互作用提供了机会。这种相互作用的一个明显例子是双向神经免疫信号，基于细胞因子、趋化因子及其受体在感觉神经元中的显著表达，以及局部免疫反应、肠-脑信号、屏障功能和宿主病原体防御的控制。这在感觉神经元的伤害受体亚群中最为明显，我们的工作强调了瞬时受体电位（TRP）通道和通过p38MAPK的下游信号在这些事件中的关键作用。该项目将以这些研究为基础，利用Metrion Biosciences在离子通道药物发现方面的丰富经验，进一步研究TRPA1在细胞因子激活肠道伤害感受器中的作用，以及它们在小鼠和人类组织以及IPSCs中对肠道屏障功能的双向调节。

BBSRC strategic theme: Understanding the rules of lifeSensory neurones are critical to the detection of environmental and internal stimuli within the gastrointestinal tract mediating physiological responses such as pain and satiety in response to noxious, inflammatory, metabolic and microbial stimuli. In addition to mediating reflex responses along the gut-brain axis, the effector functions of sensory afferents mediated through the release of signalling molecules from the afferent terminals play a key role in shaping localised interactions with the microbiome, immune cells, enteric neurons and barrier function at the mucosal interface.Data from our recent single cell RNAseq study of colonic neurones has provided comprehensive insight into the previously unrecognised diversity of mediator expression with different sensory nerve populations and opportunity for interaction with a diverse range of cell populations and signalling pathways within the bowel. One clear example of this interaction is bidirectional neuroimmune signalling based on the marked expression of cytokines, chemokines and their receptors in sensory neurons, and control of local immune response, gut-brain signalling, barrier function and host pathogen defence. This is most apparent for the nociceptor subpopulation of sensory neurons and our work has highlighted a key role for transient receptor potential (TRP) channels and downstream signalling via p38MAPK in these events. This project will build on these studies utilising the extensive experience of Metrion Biosciences in ion channel drug discovery to investigate further the role of TRPA1 in the activation of gut nociceptors by cytokines and their bidirectional regulation of gut barrier function in mouse and human tissue and IPSCs.