Neuroimmune regulation of gut function

BBSRC战略主题：了解生命的规则感觉神经元对于检测胃肠道内的环境和内部刺激至关重要，介导生理反应，如疼痛和饱腹感，以响应有害、炎症、代谢和微生物刺激。除了介导沿着肠-脑轴的反射反应之外，通过从传入末梢释放信号传导分子介导的感觉传入的效应器功能在形成与微生物组、免疫细胞、我们最近对结肠神经元的单细胞RNAseq研究的数据提供了对以前肠神经元和粘膜界面屏障功能的全面了解。不同感觉神经群体的介质表达的未识别多样性以及与肠内多种细胞群体和信号传导途径相互作用的机会。这种相互作用的一个明显例子是基于细胞因子、趋化因子及其受体在感觉神经元中的显著表达的双向神经免疫信号传导，以及局部免疫反应、肠-脑信号传导、屏障功能和宿主病原体防御的控制。这对于感觉神经元的伤害感受器亚群是最明显的，并且我们的工作突出了瞬时受体电位（TRP）通道和通过p38MAPK的下游信号传导在这些事件中的关键作用。该项目将在这些研究的基础上，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TRPA 1在细胞因子激活肠道伤害感受器中的作用，以及它们对小鼠和人体组织和IPSC中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.