Deciphering Ion Channel Mechanisms Underlying Mechanosensitivity in the Gut

破译肠道机械敏感性背后的离子通道机制

• 批准号: 10454279
• 负责人: Hongzhen Hu
• 金额: $ 48.55万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-15 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10454279
• 关键词: Acetylcholine; Affect; Afferent Neurons; Behavioral; Biochemical; Bolus Infusion; Brain; Cell Lineage; Cell physiology; Cells; Chemicals; Clinic; Colon; Congenital neurologic anomalies; Constipation; Cues; Data; Disease; Drug Targeting; Enteral; Enteric Nervous System; Enterochromaffin Cells; Epithelial; Epithelial Cells; Frequencies; Gastrointestinal Motility; Gastrointestinal Transit; Gastrointestinal tract structure; Generations; Goals; Hearing; Image; Immunofluorescence Immunologic; In Situ Hybridization; Intestines; Ion Channel; Knock-out; Knowledge; Laws; Light; Mechanics; Mediating; Mediator of activation protein; Medicine; Membrane; Methods; Migrating Myoelectric Complex; Modeling; Molecular; Motor; Movement; Mus; Muscle Contraction; Muscle relaxation phase; Neurons; Neurotransmitters; Nitrergic Neurons; Nitric Oxide; Organ; Pain; Pattern; Pharmacology; Physiological Processes; Piezo 1 ion channel; Piezo 2 ion channel; Piezo ion channels; Pilot Projects; Play; Process; Productivity; Publishing; Quality of life; Reflex action; Resolution; Role; Serotonin; Signal Transduction; Skin; Smooth Muscle Myocytes; Structure; Sturnus vulgaris; Substance P; Testing; Therapeutic; Time; Touch sensation; Vasoactive Intestinal Peptide; Visceral; base; cell motility; cholinergic; cholinergic neuron; clinically relevant; excitatory neuron; gastrointestinal epithelium; genetic approach; in vivo; inhibitor; inhibitory neuron; interdisciplinary approach; intestinal epithelium; mechanical force; mechanotransduction; motility disorder; motor behavior; mouse genetics; neural circuit; nodal myocyte; novel therapeutic intervention; patch clamp; relating to nervous system; sensor

Gastrointestinal (GI) motility is controlled by intestinal pacemaker cells, smooth muscle cells and the enteric nervous system (ENS) acting independently as the “second brain” in the gut. ENS abnormalities cause many GI motility disorders. In 1899, Bayliss and Starling proposed the classic “The law of the intestine” stating that “excitation at any point of the gut excites contraction above, inhibition below”, suggesting that distinct intrinsic excitatory and inhibitory intestinal motor behaviors can be elicited by mechanical forces. Recent studies have also demonstrated that mechanosensitivity is required to drive intestinal motor behaviors such as the colonic migrating motor complex (CMMC) resulting from either direct activation of ENS or by serotonin release from enterochromaffin cells (ECs) in the gut epithelium by mechanical forces. However, the molecules, cells, and neural circuits governing the process of mechanosensitivity in the gut still remain poorly understood. Membrane-bound ion channels play an essential role in mechanotransduction. Recent exciting studies have identified the mechanosensitive Piezo channels as molecular sensors for mechanical forces in the skin and have significantly advanced our knowledge about the role of the Piezo channels in our senses of light touch and mechanical pain. However, The role of Piezo channels involved in the mechanosensitivity in the gut and other visceral organs is poorly understood. Preliminary studies showed that chemical activation of Piezo1 promotes colon contraction and increases CMMC frequency, suggesting that Piezo1 is functionally expressed by both cholinergic excitatory and nitrergic enteric neural circuits. More importantly, Piezo1 is required for normal colonic motility in vivo. We thus hypothesize that Piezo1 is a molecular sensor for mechanical forces in the GI tract and potentially could serve as a therapeutic drug target for treating GI motility disorders such as slow transit constipation. To test this hypothesis, we will take a multidisciplinary approach using live-cell Ca2+ imaging, patch-clamp recordings and pharmacological approaches in combination to mouse genetics and intestinal motor behavioral methods to elucidate the cellular and molecular mechanisms underlying the Piezo1-mediated mechanosensitivity in both ENS and intestinal epithelium. Successful completion of these studies will advance our understanding of the previously unrecognized roles of Piezo1 and Piezo1-expressing enteric neurons and ECs in controlling GI motility. More importantly, these studies will offer new opportunities for developing effective and safer medicines for GI motility disorders.

胃肠道（GI）运动能够由肠道起搏器细胞，平滑肌细胞和Enter控制 神经系统（ENS）在肠道中独立起作用作为“第二大脑”。 ENS异常引起许多 胃肠道运动障碍。 1899年，贝利斯（Bayliss）和斯塔琳（Starling “在上面的肠道兴奋合同的任何点上的兴奋，下面的抑制作用”，表明独特的内在 兴奋性和抑制性肠道运动行为可以由机械力引起。最近的研究 还证明需要机械敏感性才能驱动肠道运动行为，例如结肠 由ENS的直接激活或5-羟色胺从释放中引起的迁移运动复合物（CMMC） 机械力在肠道上皮中的肠球毒细胞（ECS）。但是，分子，细胞和 肠道机理敏感过程的神经回路仍然知之甚少。 膜结合的离子通道在机械转导中起着至关重要的作用。最近的令人兴奋的研究已经 将机械传感器确定为皮肤机械力的分子传感器， 我们对压电通道在轻触感中的作用的认识大大提高了我们的知识 和机械疼痛。但是，压电通道在肠道中涉及机理敏感性的作用和 其他内脏器官的理解很少。初步研究表明，压电的化学激活 促进结肠收缩并增加CMMC频率，表明PIEZO1在功能上表达 通过胆碱能兴奋性和硝化肠​​神经回路。更重要的是，需要压电 体内正常结肠运动。因此，我们假设Piezo1是一种用于机械力的分子传感器 胃肠道和潜在的胃肠道可以作为治疗GI运动障碍（例如 慢速交通便秘。 为了检验这一假设，我们将使用活细胞CA2+成像，贴片钳采用多学科的方法 记录和药物方法结合了小鼠遗传学和肠道运动行为 阐明压电1介导的细胞和分子机制的方法 ENS和肠上皮的机械敏度。这些研究的成功完成将进步 我们对piezo1和表达压电1的以前无法识别的作用的理解输入神经元， 控制胃肠道运动的EC。更重要的是，这些研究将为发展提供新的机会 胃肠道运动障碍的有效和安全的药物。