Understanding Mechanisms and Sex-Differences in Visceral Pain

了解内脏疼痛的机制和性别差异

• 批准号: 10635564
• 负责人: HOLLY A. INGRAHAM
• 金额: $ 87.57万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10635564
• 关键词: Acute; Affect; Afferent Neurons; Anabolism; Anatomy; Basic Science; Brain Diseases; Cells; Chemicals; Chronic; Colitis; Colon; Communication; Data; Data Set; Diet; Disease; Endogenous Factors; Enterochromaffin Cells; Environmental Risk Factor; Enzymes; Esthesia; Estrogen Receptor alpha; Estrogens; Exhibits; Female; Functional disorder; Genetic; Genetic Models; Genetic Transcription; High Fat Diet; Hormones; Human Characteristics; Hypersensitivity; Inflammatory; Ingestion; Intestinal Diseases; Intestines; Irritable Bowel Syndrome; Irritants; Lipids; Maintenance; Mediating; Mediator; Modeling; Molecular; Mucous Membrane; Mus; Nature; Nerve Fibers; Nervous System; Organoids; Pain; Pain Threshold; Pathology; Patients; Persistent pain; Pharmacology; Pharmacology Study; Phase; Physiological; Physiology; Population; Property; Proteomics; Public Health; Quality of life; Rectum; Reporting; Role; Science; Sensory; Serotonin; Sex Differences; Signal Transduction; Sorting; Stimulus; Syndrome; Testing; Time; Tissues; Visceral; Visceral pain; Woman; Work; afferent nerve; alternative treatment; antagonist; biophysical analysis; biophysical properties; chronic pain; cohort; design; designer receptors exclusively activated by designer drugs; gut microbes; gut microbiota; gut-brain axis; high reward; high risk; hormonal signals; innovation; interest; intestinal epithelium; intravital imaging; male; microbiome; mutant; neurophysiology; novel; potential biomarker; pre-clinical; receptor; rectal; response; sex disparity; tissue injury; transcriptome sequencing

Project Summary/Abstract Our current understanding of mechanisms underlying visceral hypersensitivity, such as that associated with irritable bowel syndrome (IBS), remains rudimentary. Importantly, treating this and other functional gut disorders is limited, with a clear need for alternative treatment options. For the growing population afflicted by IBS, GI hypersensitivity and pain persist long after signs of tissue injury have resolved. Unlike other intestinal disorders, patients with IBS are hypersensitive with a lower pain threshold following colonic rectal distention (CRD) testing. Identifying the molecular and cellular components that mediate both the acute and persistent phases of visceral pain is a critical first step in understanding how environmental and endogenous factors produce long-term changes in the nervous system or associated tissues to engender chronic pain syndromes. In this new multi-PI application, we have taken a team-science approach and a multifaceted strategy designed to maximize the relevance of our pre-clinical basic research discoveries. Enterochromaffin (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. Our group recently established that EC cell-mucosal afferent signaling is a major mediator of visceral pain. We also show that the strength of this signal differs in males versus females. We will leverage our new colitis-free chemogenetic model of visceral hypersensitivity to zero in on the contribution of EC cells to visceral pain and identify molecular mechanisms through which these cells modulate the activity of nearby sensory nerve fibers. We will also ask how estrogen signaling contributes to the strong female bias that is characteristic of human IBS. Our team brings expertise in neurophysiology, pharmacology, visceral tissue anatomy, sex differences, and hormone signaling in female physiology and an unusually wide-ranging set of innovative approaches to tackle a prevalent gut-brain disorder.

项目摘要/摘要 我们目前对内脏超敏反应机制的理解，例如 肠易激综合症（IBS）仍然是基本的。重要的是，治疗这种和其他功能性肠道疾病 是有限的，清楚地需要替代治疗选择。对于不断增长的IBS的人口，GI 超敏反应和疼痛在组织损伤迹象后持续很长时间。与其他肠道疾病不同， IBS患者过敏，结肠直肠延伸（CRD）测试后疼痛阈值较低。 识别介导内脏急性和持续阶段的分子和细胞成分 疼痛是了解环境和内源性因素如何长期产生的关键第一步 神经系统或相关组织的变化导致慢性疼痛综合征。在这个新的多pi中 应用程序，我们采用了团队科学方法和一种多方面的策略，旨在最大化 我们的临床前基础研究发现的相关性。 肠球胶质素（EC）细胞是肠上皮中的关键感觉细胞，将5-羟色胺释放到原发性 感觉神经纤维，从而唤起对腔刺激物的不适和疼痛的感觉， 作为细菌代谢物，炎症剂或摄入的化学物质。我们的小组最近确定了EC 细胞粘膜传入信号传导是内脏疼痛的主要介体。我们还表明了这个信号的强度 男性与女性不同。我们将利用内脏的新的无结肠炎化学模型 EC细胞对内脏疼痛的贡献的零过敏性和鉴定分子机制的贡献 这些细胞通过其中调节附近的感觉神经纤维的活性。我们还将问雌激素 信号传导有助于人类IBS的强烈女性偏见。 我们的团队带来了神经生理学，药理学，内脏组织解剖学，性别差异和 女性生理学中的激素信号传导以及一组异常广泛的创新方法来应对 普遍的肠道障碍。