Mapping gut-spinal cord connections in visceral pain

项目摘要/摘要 我们目前对内脏疼痛潜在机制的理解，包括与应激相关的机制 肠道综合征，仍处于初级阶段。重要的是，鸦片类药物在治疗内脏疼痛综合征方面无效， 而且只会通过产生便秘而加剧不适，反映出明显需要替代治疗 选择。这项提议的目标是给这一未得到充分利用的疼痛研究领域带来更大的机械性洞察力， 并以多方面的策略处理这一问题，以最大限度地提高我们基础研究的相关性 未来疼痛治疗的新发现。在这里，我们将询问肠嗜铬细胞(EC)如何传递有害信号 从肠腔到脊髓。EC细胞是肠道上皮细胞释放的关键感觉细胞 5-羟色胺在初级感觉神经纤维上，从而引起不适和疼痛的感觉 腔刺激物，如细菌代谢物、发炎剂或摄入的化学物质。这样做的目的是 协作工作是使用激活和静默方法来检查 EC细胞和感觉神经纤维。我们将把这些方法与转录组分析、病毒追踪和 电生理学方法，以深入了解这些纤维的分子和功能特性。另一个 关键目标是确定EC细胞信号通路是否表现出性别差异，这是一个重要的 这个问题可能与女性经历的胃肠道内脏疼痛综合征的患病率较高有关。 我们的团队为这一疼痛研究领域带来了异常广泛和创新的方法 包括神经生理学、药理学、伤害性和痛觉回路、内脏的解剖学方面的专业知识。 组织解剖与发育及相关临床经验。此知识库由以下项目支持 互补的技术方法，使我们能够将分子和机械洞察力连接到 生理学、内脏伤害感和疾病。 我们对上皮-伤害性感受器连接体的关注突出了EC和其他肠道内分泌细胞类型，如 对内脏不适和疼痛进行神经调节的潜在强大控制点。一个全面的 EC-初级传入-脊髓回路的功能、药理学、遗传学和解剖学特征是一个 这是实现这一重要目标的重要第一步。因此，我们的研究计划完全符合 SPARC的任务是改变我们对周围神经-器官相互作用的理解并推进战略 用来控制器官系统的功能。

Project Summary/Abstract Our current understanding of mechanisms underlying visceral pain, including that associated with irritable bowel syndrome, remains rudimentary. Importantly, opiates are ineffective at treating visceral pain syndromes, and only exacerbate discomfort by producing constipation, reflecting a clear need for alternative treatment options. The goal of this proposal is to bring greater mechanistic insight to this underserved area of pain research, and to approach the problem in a multifaceted strategy designed to maximize the relevance of our basic research discoveries to future pain treatments. Here, we will ask how enterochromaffin (EC) cells transmit noxious signals from the gut lumen to the spinal cord. EC cells are key sensory cells in the intestinal epithelium that release serotonin onto primary sensory nerve fibers, thereby evoking a sensation of discomfort and pain in response to luminal irritants, such as bacterial metabolites, inflammatory agents, or ingested chemicals. The goals of this collaborative effort are to use activating and silencing approaches to examine functional connections between EC cells and sensory nerve fibers. We will couple these methods with transcriptome profiling, viral tracing, and electrophysiological methods to gain insights into the molecular and functional identity of these fibers. Another key goal is to determine whether EC cell signaling pathways exhibit sex-specific differences, an important question that may relate to the higher prevalence of GI visceral pain syndromes experienced by women. Our team brings an unusually wide ranging and innovative approach to this area of pain research that includes expertise in the neurophysiology, pharmacology, and anatomy of nociceptive and pain circuits, visceral tissue anatomy and development, and relevant clinical experience. This knowledge base is supported by complementary technological approaches that will enable us to connect molecular and mechanistic insights to physiology, visceral nociception, and disease. Our focus on the epithelial-nociceptor connectome highlights EC and other enteroendocrine cell types as potentially powerful control points for neuromodulation of visceral discomfort and pain. A comprehensive functional, pharmacological, genetic and anatomical characterization of EC-primary afferent-spinal circuits is an essential first step toward achieving this important goal. As such, our research program fits squarely within the SPARC mandate to transform our understanding of peripheral nerve-organ interactions and advance strategies for controlling organ system function.