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
基本信息
- 批准号:10454279
- 负责人:
- 金额:$ 48.55万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:AcetylcholineAffectAfferent NeuronsBehavioralBiochemicalBolus InfusionBrainCell LineageCell physiologyCellsChemicalsClinicColonCongenital neurologic anomaliesConstipationCuesDataDiseaseDrug TargetingEnteralEnteric Nervous SystemEnterochromaffin CellsEpithelialEpithelial CellsFrequenciesGastrointestinal MotilityGastrointestinal TransitGastrointestinal tract structureGenerationsGoalsHearingImageImmunofluorescence ImmunologicIn Situ HybridizationIntestinesIon ChannelKnock-outKnowledgeLawsLightMechanicsMediatingMediator of activation proteinMedicineMembraneMethodsMigrating Myoelectric ComplexModelingMolecularMotorMovementMusMuscle ContractionMuscle relaxation phaseNeuronsNeurotransmittersNitrergic NeuronsNitric OxideOrganPainPatternPharmacologyPhysiological ProcessesPiezo 1 ion channelPiezo 2 ion channelPiezo ion channelsPilot ProjectsPlayProcessProductivityPublishingQuality of lifeReflex actionResolutionRoleSerotoninSignal TransductionSkinSmooth Muscle MyocytesStructureSturnus vulgarisSubstance PTestingTherapeuticTimeTouch sensationVasoactive Intestinal PeptideVisceralbasecell motilitycholinergiccholinergic neuronclinically relevantexcitatory neurongastrointestinal epitheliumgenetic approachin vivoinhibitorinhibitory neuroninterdisciplinary approachintestinal epitheliummechanical forcemechanotransductionmotility disordermotor behaviormouse geneticsneural circuitnodal myocytenovel therapeutic interventionpatch clamprelating to nervous systemsensor
项目摘要
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) 运动由肠道起搏细胞、平滑肌细胞和肠道细胞控制。
神经系统(ENS)作为肠道中的“第二大脑”独立运作,ENS 异常会导致许多问题。
1899年,Bayliss和Starling提出了经典的“肠道法则”,指出:
“肠道任何一点的兴奋都会激发上方的收缩,下方的抑制”,这表明不同的内在机制
最近的研究表明,机械力可以引发兴奋性和抑制性肠道运动行为。
还表明,驱动肠道运动行为(如结肠)需要机械敏感性
迁移运动复合体 (CMMC) 是由 ENS 的直接激活或由 ENS 释放的血清素引起的
肠道上皮中的肠嗜铬细胞(EC)受到机械力的作用,然而,分子、细胞和。
控制肠道机械敏感性过程的神经回路仍然知之甚少。
膜结合离子通道在力传导中发挥着重要作用。
确定了机械敏感压电通道作为皮肤机械力的分子传感器,
显着提高了我们对压电通道在轻触感中的作用的认识
然而,压电通道的作用涉及肠道和机械敏感性。
对其他内脏器官的了解还知之甚少,初步研究表明 Piezo1 的化学激活作用。
促进结肠收缩并增加 CMMC 频率,表明 Piezo1 具有功能性表达
更重要的是,Piezo1 是胆碱能兴奋性和氮能肠神经回路所必需的。
因此,我们发现 Piezo1 是体内机械力的分子传感器。
胃肠道,可能作为治疗胃肠道运动障碍的药物靶点,例如
慢传输型便秘。
为了验证这一假设,我们将采用多学科方法,使用活细胞 Ca2+ 成像、膜片钳
记录和药理学方法结合小鼠遗传学和肠道运动行为
阐明 Piezo1 介导的细胞和分子机制的方法
ENS 和肠上皮的机械敏感性的成功完成将推进。
我们对 Piezo1 和表达 Piezo1 的肠神经元以前未被认识到的作用的理解
更重要的是,这些研究将为控制胃肠道运动提供新的机会。
治疗胃肠道动力障碍的有效且更安全的药物。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Hongzhen Hu其他文献
Hongzhen Hu的其他文献
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{{ truncateString('Hongzhen Hu', 18)}}的其他基金
Genetic analysis of intrinsic sensory neuron function in the enteric neural circuits
肠神经回路中内在感觉神经元功能的遗传分析
- 批准号:
10568622 - 财政年份:2023
- 资助金额:
$ 48.55万 - 项目类别:
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:
10889525 - 财政年份:2023
- 资助金额:
$ 48.55万 - 项目类别:
Deciphering the Piezo2-Merkel cell signaling mechanisms in itch
破译瘙痒中的 Piezo2-Merkel 细胞信号传导机制
- 批准号:
10890431 - 财政年份:2023
- 资助金额:
$ 48.55万 - 项目类别:
Deciphering the Piezo2-Merkel cell signaling mechanisms in itch
破译瘙痒中的 Piezo2-Merkel 细胞信号传导机制
- 批准号:
10676917 - 财政年份:2020
- 资助金额:
$ 48.55万 - 项目类别:
Deciphering the Piezo2-Merkel cell signaling mechanisms in itch
破译瘙痒中的 Piezo2-Merkel 细胞信号传导机制
- 批准号:
10454374 - 财政年份:2020
- 资助金额:
$ 48.55万 - 项目类别:
Deciphering the Piezo2-Merkel cell signaling mechanisms in itch
破译瘙痒中的 Piezo2-Merkel 细胞信号传导机制
- 批准号:
10225638 - 财政年份:2020
- 资助金额:
$ 48.55万 - 项目类别:
MECHANISMS OF TRPV4-MEDIATED NEUROPATHIC PAIN
TRPV4 介导的神经病理性疼痛的机制
- 批准号:
10204872 - 财政年份:2018
- 资助金额:
$ 48.55万 - 项目类别:
MECHANISMS OF TRPV4-MEDIATED NEUROPATHIC PAIN
TRPV4 介导的神经病理性疼痛的机制
- 批准号:
10443627 - 财政年份:2018
- 资助金额:
$ 48.55万 - 项目类别:
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:
10116046 - 财政年份:2015
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8962583 - 财政年份:2015
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