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.

项目概要/摘要 我们目前对内脏过敏机制的理解，例如与内脏过敏相关的机制 肠易激综合症（IBS）仍然处于初级阶段。重要的是，治疗这种疾病和其他功能性肠道疾病 是有限的，显然需要替代治疗方案。对于不断增长的肠易激综合症 (IBS)、胃肠道综合症 (GI) 患者 在组织损伤迹象消失后很长一段时间内，过敏和疼痛仍持续存在。与其他肠道疾病不同， IBS 患者在结肠直肠扩张 (CRD) 测试后过敏，疼痛阈值较低。 识别介导内脏急性期和持续期的分子和细胞成分 疼痛是了解环境和内源性因素如何产生长期影响的关键第一步 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 应用程序中，我们采取了团队科学的方法和多方面的策略，旨在最大限度地提高 我们的临床前基础研究发现的相关性。 肠嗜铬细胞 (EC) 是肠上皮中的关键感觉细胞，可将血清素释放到原代细胞上。 感觉神经纤维，从而引起对管腔刺激物的不适和疼痛感，例如 作为细菌代谢物、炎症剂或摄入的化学物质。我们小组最近建立了 EC 细胞粘膜传入信号传导是内脏疼痛的主要介质。我们还表明该信号的强度 男性与女性有所不同。我们将利用我们新的内脏无结肠炎化学遗传学模型 EC 细胞对内脏疼痛的贡献为零，并确定分子机制 这些细胞通过它们调节附近感觉神经纤维的活动。我们还会询问雌激素如何 信号传导导致强烈的女性偏见，这是人类肠易激综合症的特征。 我们的团队拥有神经生理学、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系列异常广泛的创新方法来解决 流行的肠脑疾病。