Mapping gut-spinal cord connections in visceral pain

绘制内脏疼痛中的肠-脊髓连接图

基本信息

批准号：
10023951
负责人：
HOLLY A. INGRAHAM
金额：
$ 79.55万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
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：
2019-09-23 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10023951
关键词：
Acute Affect Afferent Neurons Anatomy Animals Area Basic Science Brain Cell Count Cells Cellular Structures Chemicals Colon Constipation Cutaneous Development Disease Disease model Electrophysiology (science)Enterochromaffin Cells Enteroendocrine Cell Enzymes Epithelial Epithelial Cells Epithelium Esthesia Estrogen Receptors Estrogen receptor positive Estrogens Estrus Exhibits Female Fiber Future Gastrointestinal tract structure Genes Genetic Goals Heterogeneity High Prevalence Hormones Human Inflammatory Ingestion Intestines Irritable Bowel Syndrome Irritants Knock-out Label Maps Measures Mechanics Methods Modality Molecular Mus Nerve Endings Nerve Fibers Neuraxis Neurons Nociception Nociceptors Opioid Opioid Analgesics Organ Organoids Pain Pain Research Pain management Pathway interactions Peripheral Nerves Persistent pain Pharmacology Physiological Physiology Prevalence Proteins Public Health Rabies virus Research Rodent Sampling Sensory Sensory Ganglia Serotonin Sex Differences Signal Pathway Signal Transduction Sorting - Cell Movement Spinal Spinal Cord Spinal cord posterior horn Stimulus Synapses Syndrome Techniques Testing Tissues Translating Viral Visceral Visceral Afferents Visceral pain Woman Work addiction afferent nerve aged alternative treatment anatomical tracing body system cell type clinically relevant colorectal distension connectome design designer receptors exclusively activated by designer drugs experience gastrointestinal genetic approach innovation insight intestinal epithelium knowledge base male men mouse model neurophysiology neuroregulation novel therapeutics programs receptor receptor expression response transcriptome

Acute Affect Afferent Neurons Anatomy Animals Area Basic Science Brain Cell Count Cells Cellular Structures Chemicals Colon Constipation Cutaneous Development Disease Disease model Electrophysiology (science)Enterochromaffin Cells Enteroendocrine Cell Enzymes Epithelial Epithelial Cells Epithelium Esthesia Estrogen Receptors Estrogen receptor positive Estrogens Estrus Exhibits Female Fiber Future Gastrointestinal tract structure Genes Genetic Goals Heterogeneity High Prevalence Hormones Human Inflammatory Ingestion Intestines Irritable Bowel Syndrome Irritants Knock-out Label Maps Measures Mechanics Methods Modality Molecular Mus Nerve Endings Nerve Fibers Neuraxis Neurons Nociception Nociceptors Opioid Opioid Analgesics Organ Organoids Pain Pain Research Pain management Pathway interactions Peripheral Nerves Persistent pain Pharmacology Physiological Physiology Prevalence Proteins Public Health Rabies virus Research Rodent Sampling Sensory Sensory Ganglia Serotonin Sex Differences Signal Pathway Signal Transduction Sorting - Cell Movement Spinal Spinal Cord Spinal cord posterior horn Stimulus Synapses Syndrome Techniques Testing Tissues Translating Viral Visceral Visceral Afferents Visceral pain Woman Work addiction afferent nerve aged alternative treatment anatomical tracing body system cell type clinically relevant colorectal distension connectome design designer receptors exclusively activated by designer drugs experience gastrointestinal genetic approach innovation insight intestinal epithelium knowledge base male men mouse model neurophysiology neuroregulation novel therapeutics programs receptor receptor expression response transcriptome

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项目摘要

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.

项目摘要/摘要我们目前对内脏疼痛的机制的理解，包括与烦躁有关的机制肠综合症，仍然是基本的。重要的是，阿片类药物无效治疗内脏疼痛综合征，并且只会通过产生便秘加剧不适，这反映了对替代治疗的明显需求选项。该提案的目的是为这一服务不足的疼痛研究领域带来更大的机械洞察力，并在旨在最大化基础研究相关性的多方面策略中解决问题发现未来的疼痛治疗。在这里，我们将询问肠球毒蛋白（EC）细胞如何传输有害信号从肠道到脊髓。 EC细胞是肠上皮中的关键感觉细胞 5-羟色胺上原发性感觉神经纤维，从而引起不适感和疼痛的感觉腔刺激物，例如细菌代谢物，炎症剂或摄入的化学物质。目标的目标协作努力是使用激活和沉默方法来检查 EC细胞和感觉神经纤维。我们将将这些方法与转录组分析，病毒跟踪和电生理方法可以洞悉这些纤维的分子和功能认同。其他关键目标是确定EC细胞信号通路是否表现出性别特异性差异，这是一个重要的可能与女性经历的GI内脏疼痛综合症患病率更高有关的问题。我们的团队为这一痛苦研究领域带来了异常广泛的创新方法包括神经生理学，药理学和伤害性和疼痛回路的专业知识，内脏组织解剖学和发育以及相关的临床经验。这个知识库得到了互补的技术方法将使我们能够将分子和机械洞察力连接到生理，内脏伤害感和疾病。我们关注上皮无害感受器Connectome，将EC和其他肠内docrine细胞类型重点介绍为内脏不适和疼痛神经调节的潜在强大控制点。全面 EC主要传入脊髓回路的功能，药理，遗传和解剖表征是一种实现这一重要目标的第一步。因此，我们的研究计划完全适合 SPARC的任务是改变我们对周围神经和器官相互作用的理解并提高策略用于控制器官系统功能。