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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：
Hongzhen Hu
金额：
$ 48.55万
依托单位：
WASHINGTON UNIVERSITY
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：
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

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.

胃肠运动是由肠起搏器细胞、平滑肌细胞和肠组织控制的