Linkage of s100a10 (p11) to enteric 5-HT4-mediated serotonergic signaling roles in GI motility, enteric nervous system development, and co-morbid dysfunction of gut and brain

s100a10 (p11) 与肠道 5-HT4 介导的血清素信号在胃肠道运动、肠神经系统发育以及肠道和大脑共病功能障碍中的作用的联系

• 批准号: 10755945
• 负责人: Kara Gross Margolis
• 金额: $ 47.77万
• 依托单位: NEW YORK UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-01 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10755945
• 关键词: 5-Hydroxytryptophan; Affect; Age Months; Agonist; Anabolism; Anxiety; Biotinylation; Brain; Bypass; Cell membrane; Cell surface; Central Nervous System; Clinical; Co-Immunoprecipitations; Comprehension; Constipation; Curiosities; Data; Defect; Development; Disease; Economic Burden; Educational workshop; Enteral; Enteric Nervous System; Environmental Exposure; Enzymes; Epithelial Cells; Epithelium; Exhibits; Failure; Functional Gastrointestinal Disorders; Functional disorder; Gastrointestinal Motility; Gastrointestinal tract structure; Genetic; Genetic Transcription; High Prevalence; Human; Immunofluorescence Immunologic; Impairment; Individual; Intestinal Mucosa; Intestines; Irritable Bowel Syndrome; Knowledge; Lead; Lesion; Life; Maintenance; Mediating; Membrane; Mental Depression; Molecular; Mood Disorders; Moods; Mucous Membrane; Mus; Neurons; Pathogenesis; Patients; Phenotype; Play; Prevalence; Quality of life; Role; Serotonergic System; Serotonin; Serotonin Receptors 5-HT4; Signal Transduction; Signaling Molecule; Site; Suggestion; Symptoms; TPH2; Testing; Transgenic Mice; Treatment Failure; United States National Institutes of Health; Variant; affective disturbance; analog; antinociception; brain dysfunction; comorbidity; cost; depression model; depressive behavior; depressive symptoms; design; effective therapy; gastrointestinal; gastrointestinal function; genetic variant; improved; in vivo; motility disorder; mouse model; nervous system development; neurogenesis; neuron development; novel; novel therapeutics; pre-clinical; psychiatric comorbidity; receptor; suicide victim; trafficking

Project Summary Although functional gastrointestinal (GI) disorders (FGIDs) are the most common causes of bowel dysfunction worldwide, many patients are inadequately treated because current therapies are frequently ineffective. The inadequacy of therapy is largely due to an incomplete comprehension of underlying mechanisms that are critical for the design of new treatments. Up to half of individuals with FGIDs also suffer from mood disorders. Evidence supports the idea that the GI tract is vulnerable to genetic perturbations that can exert lasting effects on GI function and mood. It is thus conceivable that a co-morbid FGID and psychiatric condition result from abnormalities occurring as the result of a genetic variant. Discovery of the pathophysiology underlying FGIDs and psychiatric co-morbidities is likely to enhance understanding of their relationship and thus lead to novel therapies for both. Serotonin (5-HT), which is a major determinant of enteric and central nervous system (ENS and CNS) development and also modulates FGID-related symptoms (GI motility) as well as mood, may be an important developmental modulator of FGID pathogenesis. It is 5-HT stimulation of the 5-HT4 receptor, however, that has the most well-studied prokinetic, anti-nociceptive, anti- depressive, and anti-anxiety effects and has thus been targeted to treat both GI dysmotility and mood dysfunction. Curiously, however, >50% of patients with FGIDs are relatively unresponsive to them. The reason for 5-HT4 treatment failure is unknown, making this a critical treatment obstacle. Our preliminary data strongly suggest that failure to respond to a 5-HT4 agonist is due to a defect in 5-HT4 trafficking. Although defects in enteric 5-HT4 trafficking have never previously been explored, such abnormalities have been described in the CNS; p11 is a critical adaptor molecule involved in this transport of 5-HT4 receptors to cell surfaces, where the receptors become available to mediate 5-HT signaling. P11 also plays a role in depression (p11KO mice exhibit depressive behaviors and CNS p11 transcription is impaired in mouse models of depression and human suicide victims). We have found that in the ENS, as in the CNS, gut p11 is co- expressed with 5-HT4 receptors where they co-immunoprecipitate, suggesting that p11 interacts with 5-HT4 in the gut and, further, that p11 affects 5-HT4 receptor-mediated actions on ENS development and GI motility. Our hypotheses are thus that p11 facilitation of trafficking of 5-HT4 receptors to cell surfaces is essential for 5-HT4- modulation of ENS development and function and that p11 dysfunction thus underlies comorbid FGID and depression. In this application we will explore: (1) How critical the p11-5-HT4 interaction is for effective GI motility utilizing a comprehensive array of in vivo and ex vivo studies ± the selective 5-HT4 agonist, prucalopride, in WT and p11KO mice; (2) If effects of p11 on mood (depression / anxiety), ENS development, and GI motility depend on mucosal or enteric neuronal p11, using novel transgenic mice that selectively lack p11 in the enteric epithelium or ENS and; (3) If enteric 5-HT4 trafficking and function are p11-dependent.

项目概要 尽管功能性胃肠道 (GI) 疾病 (FGID) 是肠道最常见的原因 世界范围内的功能障碍，许多患者没有得到充分的治疗，因为目前的治疗方法经常是 无效。治疗的不足很大程度上是由于对潜在的理解不完全造成的。 对于新疗法的设计至关重要的机制。多达一半的 FGID 患者也患有这种疾病 来自情绪障碍。有证据支持这样的观点：胃肠道容易受到遗传扰动的影响 可以对胃肠道功能和情绪产生持久影响。因此可以想象，FGID 和精神疾病共存。 疾病是由遗传变异导致的异常引起的。发现 FGID 和精神共病的病理生理学可能会增强对其的了解 关系，从而为两者带来新的疗法。血清素（5-HT）是肠溶的主要决定因素 和中枢神经系统（ENS 和 CNS）发育，还调节 FGID 相关症状（GI 运动性）以及情绪，可能是 FGID 发病机制的重要发育调节因子。它是5-HT 然而，刺激 5-HT4 受体具有最充分研究的促动力、抗伤害性、抗 具有抑郁和抗焦虑作用，因此被用于治疗胃肠道运动障碍和情绪 功能障碍。然而奇怪的是，超过 50% 的 FGID 患者对它们的反应相对较弱。这 5-HT4 治疗失败的原因尚不清楚，这使其成为一个关键的治疗障碍。我们的初步数据 强烈表明对 5-HT4 激动剂无反应是由于 5-HT4 运输缺陷所致。虽然 肠道 5-HT4 运输的缺陷以前从未被探索过，但此类异常已被 在中枢神经系统中描述； p11 是参与 5-HT4 受体向细胞转运的关键接头分子 表面，受体可用于介导 5-HT 信号传导。 P11 也在抑郁症中发挥作用 （p11KO 小鼠表现出抑郁行为，并且在小鼠模型中 CNS p11 转录受损 抑郁症和人类自杀受害者）。我们发现，在 ENS 中，就像在 CNS 中一样，肠道 p11 与 与 5-HT4 受体一起表达，并发生免疫共沉淀，表明 p11 与 5-HT4 相互作用 此外，p11 还影响 5-HT4 受体介导的 ENS 发育和胃肠道运动。我们的 因此，假设 p11 促进 5-HT4 受体运输至细胞表面对于 5-HT4- 至关重要。 ENS 发育和功能的调节以及 p11 功能障碍因此是共病 FGID 和 沮丧。在此应用中，我们将探讨：(1) p11-5-HT4 相互作用对于有效 GI 的重要性 利用一系列全面的体内和离体研究±选择性 5-HT4 激动剂， 普卡必利，在 WT 和 p11KO 小鼠中； (2) p11 对情绪（抑郁/焦虑）、ENS 发育的影响， 胃肠道运动依赖于粘膜或肠神经元 p11，使用选择性缺乏的新型转基因小鼠 p11 在肠上皮或 ENS 中； (3) 肠内 5-HT4 运输和功能是否依赖于 p11。