Understanding Mechanisms and Sex-Differences in Visceral Pain

项目概要/摘要 我们目前对内脏高敏感性机制的理解，例如与 肠易激综合征（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，显然需要替代治疗方案。对于越来越多的IBS患者，GI 在组织损伤迹象消失后，超敏反应和疼痛仍持续很长时间。与其他肠道疾病不同， 患有IBS的患者在结肠直肠扩张（CRD）测试后具有较低的疼痛阈值的过敏性。 确定介导内脏神经损伤急性期和持续期的分子和细胞成分 疼痛是理解环境和内源性因素如何产生长期的 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，我们采取了团队科学的方法和多方面的战略，旨在最大限度地提高 临床前基础研究发现的相关性。 肠嗜铬细胞（EC）是肠上皮细胞中的关键感觉细胞，其将5-羟色胺释放到原发性 感觉神经纤维，从而引起对管腔刺激物的不适和疼痛的感觉， 如细菌代谢物、炎症因子或摄入的化学物质。我们小组最近成立了EC 细胞-粘膜传入信号是内脏痛的主要介质。我们还表明，这种信号的强度 在男性和女性之间有不同我们将利用我们新的无结肠炎的内脏化学遗传模型， 超敏反应归零EC细胞对内脏痛的贡献，并确定分子机制 通过这些细胞调节附近感觉神经纤维的活动。我们也会问雌激素 信号传导导致强烈的女性偏好，这是人类IBS的特征。 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， 女性生理学中的激素信号，以及一套异常广泛的创新方法来解决 普遍的肠脑紊乱

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.