Deciphering Ion Channel Mechanisms Underlying Mechanosensitivity in the Gut
Deciphering Ion Channel Mechanisms Underlying Mechanosensitivity in the Gut
批准号:
10889525
负责人:
Hongzhen Hu
金额:
$48.55万
依托单位国家:
美国
项目类别:
财政年份:
2023
资助国家:
美国
项目状态:
已结题
起止时间:
2023-08-01 至 2024-07-31
中文摘要
胃肠运动是由肠起搏器细胞、平滑肌细胞和肠组织控制的
英文摘要
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.
期刊论文(19)
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DOI:
10.1039/c9ob00893d
发表时间:
2019-06
期刊:
Organic & biomolecular chemistry
影响因子:
3.2
作者:
[Yanbo Yu;Qianwa Liang;Hui Liu;Zonghua Luo;Hongzhen Hu;J. Perlmutter;Z. Tu]
通讯作者:
Yanbo Yu;Qianwa Liang;Hui Liu;Zonghua Luo;Hongzhen Hu;J. Perlmutter;Z. Tu
DOI:
10.3389/fphys.2016.00065
发表时间:
2016
期刊:
Frontiers in physiology
影响因子:
4
作者:
[Gu QD, Moss CR 2nd, Kettelhut KL, Gilbert CA, Hu H]
通讯作者:
Hu H
DOI:
10.1016/j.immuni.2018.04.021
发表时间:
2018-07-17
期刊:
Immunity
影响因子:
32.4
作者:
[Luo J, Qian A, Oetjen LK, Yu W, Yang P, Feng J, Xie Z, Liu S, Yin S, Dryn D, Cheng J, Riehl TE, Zholos AV, Stenson WF, Kim BS, Hu H]
通讯作者:
Hu H
Sensory TRP channels contribute differentially to skin inflammation and persistent itch.
感觉 TRP 通道对皮肤炎症和持续瘙痒的影响不同
DOI:
10.1038/s41467-017-01056-8
发表时间:
2017-10-30
期刊:
Nature communications
影响因子:
16.6
作者:
[Feng J, Yang P, Mack MR, Dryn D, Luo J, Gong X, Liu S, Oetjen LK, Zholos AV, Mei Z, Yin S, Kim BS, Hu H]
通讯作者:
Hu H
DOI:
10.1126/science.aar5703
发表时间:
2018-05-04
期刊:
Science (New York, N.Y.)
影响因子:
--
作者:
[Feng J, Luo J, Yang P, Du J, Kim BS, Hu H]
通讯作者:
Hu H
共 10 条
Genetic analysis of intrinsic sensory neuron function in the enteric neural circuits
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批准号:10568622
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项目类别:
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资助金额:$55.27万
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财政年份:2023
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负责人:Hongzhen Hu
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依托单位:
Deciphering the Piezo2-Merkel cell signaling mechanisms in itch
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批准号:10890431
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资助金额:$56.78万
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财政年份:2023
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负责人:Hongzhen Hu
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依托单位:
Deciphering the Piezo2-Merkel cell signaling mechanisms in itch
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批准号:10676917
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项目类别:
-
资助金额:$0.0万
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财政年份:2020
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负责人:Hongzhen Hu
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依托单位:
Deciphering the Piezo2-Merkel cell signaling mechanisms in itch
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批准号:10454374
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项目类别:
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资助金额:$52.39万
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财政年份:2020
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负责人:Hongzhen Hu
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依托单位:
Deciphering the Piezo2-Merkel cell signaling mechanisms in itch
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批准号:10225638
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项目类别:
-
资助金额:$49.42万
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财政年份:2020
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负责人:Hongzhen Hu
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依托单位:
MECHANISMS OF TRPV4-MEDIATED NEUROPATHIC PAIN
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批准号:10204872
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项目类别:
-
资助金额:$50.53万
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财政年份:2018
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负责人:Hongzhen Hu
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依托单位:
MECHANISMS OF TRPV4-MEDIATED NEUROPATHIC PAIN
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批准号:10443627
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项目类别:
-
资助金额:$50.53万
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财政年份:2018
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负责人:Hongzhen Hu
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依托单位:
Deciphering Ion Channel Mechanisms Underlying Mechanosensitivity in the Gut
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批准号:10454279
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项目类别:
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资助金额:$48.55万
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财政年份:2015
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负责人:Hongzhen Hu
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依托单位:
Deciphering Ion Channel Mechanisms Underlying Mechanosensitivity in the Gut
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批准号:10116046
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项目类别:
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资助金额:$48.55万
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财政年份:2015
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负责人:Hongzhen Hu
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TARGETING THE TRANSIENT RECEPTOR POTENTIAL CHANNELS TO IMPROVE BOWEL DYSFUNCTION
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批准号:8962583
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项目类别:
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资助金额:$35.45万
-
财政年份:2015
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负责人:Hongzhen Hu
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依托单位:
Deciphering Ion Channel Mechanisms Underlying Mechanosensitivity in the Gut
-
批准号:10263379
-
项目类别:
-
资助金额:$48.55万
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财政年份:2015
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负责人:Hongzhen Hu
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依托单位:
Mechanisms of Zinc Regulation of Pain-initiating TRP Channels
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批准号:8869234
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项目类别:
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资助金额:$26.7万
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财政年份:2014
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负责人:Hongzhen Hu
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依托单位:
Mechanisms of Zinc Regulation of Pain-initiating TRP Channels
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批准号:9068195
-
项目类别:
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资助金额:$28.98万
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财政年份:2014
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负责人:Hongzhen Hu
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依托单位:
Mechanisms of Zinc Regulation of Pain-initiating TRP Channels
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批准号:8505830
-
项目类别:
-
资助金额:$28.88万
-
财政年份:2013
-
负责人:Hongzhen Hu
-
依托单位:
国内基金
海外基金
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