Extrinsic Neural Control of Gastrointestinal Function in the Disordered Bowel

肠道紊乱胃肠功能的外在神经控制

基本信息

  • 批准号:
    8217087
  • 负责人:
  • 金额:
    $ 29.62万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2008
  • 资助国家:
    美国
  • 起止时间:
    2008-04-01 至 2013-04-30
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Postganglionic sympathetic neurons located in the prevertebral ganglia (PVG) provide ongoing sympathetic tone to the entire gastrointestinal (GI) tract. In addition, these neurons coordinate motor, secretory and vascular functions via reflexes initiated by intestinofugal afferent neurons (IFANs) located in the wall of the intestine. The overall hypothesis to be tested by these proposed studies is that the mechanisms by which information is transmitted through the PVG are altered during intestinal inflammation. Experiments proposed in this application will test this hypothesis by addressing three specific aims. Specific Aim 1 tests the hypothesis that TNBS-induced colitis causes a loss of IFANs that result in the increased expression of functional purinergic and glutamatergic ligand-gated ion channels in PVG neurons. Specific Aim 2 tests the hypothesis that the expression and function of 12A adrenergic receptors (ARs) on the terminal fields of PVG neurons in the ileum is increased following the onset of TNBS or acetic acid induced colitis. Specific Aim 3 tests the hypothesis that purinergic and glutamatergic synaptic transmission in the PVG and a change in the expression of 12A ARs during colitis result in altered motor function in the small intestine. The overall hypothesis of this proposal is supported by preliminary data indicating several distinct changes in the physiology of PVG neurons during colitis. Inflammation causes an increased excitability of PVG neurons and a change in the ionotropic receptors that contribute to fast synaptic communication. This would likely contribute to increased sympathetic outflow to the GI tract. In addition, colitis is associated with an increased expression of autoinhibitory 12A ARs on the axon terminal fields of PVG neurons. By impeding invading action potentials from causing norepinephrine release, enhanced 12A ARs would result in a reduction of sympathetic outflow to more normal levels. The temporal relationship between these changes in the physiology of PVG neurons and altered ileal motor function will elucidate potential contributing mechanisms to clinically relevant bowel dysfunction. Collectively, the experiments proposed are a systematic approach to understanding the change in function of PVG neurons during colitis. The results of these experiments are likely to provide an understanding of new mechanisms by which the physiology of PVG neurons is regulated and may provide insight to the development of novel therapeutic agents that target the PVG to regulate GI motility. Public Health Relevance: Changes in the structure and function of the nerves that supply the gastrointestinal tract contribute to both symptoms commonly encountered during intestinal inflammation, as well as symptoms that can persist long after the initial insult. Sympathetic autonomic nerve cells, which integrate signals from nerve cells in the brain and spinal cord with signals from nerve cells in the gastrointestinal tract, have not previously been studied for their contribution to altered gut function; therefore specific changes in these cells will be examined during inflammation of the large intestine, or colitis. The results of these studies are expected to provide an understanding of new mechanisms by which the nervous system control of movements of gastrointestinal contents is altered during colitis and will provide insight to the development of new therapies for the treatment of bowel dysfunction.
描述(由申请人提供):位于椎前神经节(PVG)的节后交感神经元为整个胃肠道(GI)提供持续的交感张力。此外,这些神经元通过位于肠壁的肠传入神经元(IFANs)发起的反射来协调运动、分泌和血管功能。这些拟议的研究要验证的总体假设是,在肠道炎症期间,信息通过PVG传递的机制发生了改变。本应用程序中提出的实验将通过解决三个具体目标来验证这一假设。特异性Aim 1验证了tnbs诱导的结肠炎导致IFANs缺失的假设,从而导致PVG神经元中功能性嘌呤能和谷氨酸能配体门控离子通道的表达增加。特异性目的2验证了在TNBS或醋酸性结肠炎发生后,回肠PVG神经元末端野12A肾上腺素能受体(ARs)的表达和功能增加的假设。特异性目的3验证了PVG中嘌呤能和谷氨酸能突触传递以及结肠炎期间12A ar表达变化导致小肠运动功能改变的假设。初步数据表明,结肠炎期间PVG神经元的几个明显的生理变化支持了这一提议的总体假设。炎症引起PVG神经元的兴奋性增加,并改变有助于快速突触通信的嗜离子受体。这可能会增加交感神经向胃肠道的流出。此外,结肠炎与PVG神经元轴突末端区自身抑制性12A ARs的表达增加有关。通过阻止入侵的动作电位引起去甲肾上腺素的释放,增强的12A ar将导致交感神经流出减少到更正常的水平。PVG神经元生理变化与回肠运动功能改变之间的时间关系将阐明临床相关肠功能障碍的潜在促进机制。总的来说,提出的实验是了解结肠炎期间PVG神经元功能变化的系统方法。这些实验的结果可能提供对PVG神经元生理调节的新机制的理解,并可能为开发针对PVG调节GI运动的新型治疗药物提供见解。

项目成果

期刊论文数量(8)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Enhanced excitability of guinea pig ileum myenteric AH neurons during and following recovery from chemical colitis.
  • DOI:
    10.1016/j.neulet.2013.04.021
  • 发表时间:
    2013-06-17
  • 期刊:
  • 影响因子:
    2.5
  • 作者:
    Linden DR
  • 通讯作者:
    Linden DR
Getting a handle on cholera and the circuits controlling intestinal motility.
控制霍乱和控制肠道蠕动的回路。
  • DOI:
    10.3389/fnins.2010.00197
  • 发表时间:
    2010
  • 期刊:
  • 影响因子:
    4.3
  • 作者:
    Bertrand,PaulP;Linden,DavidR
  • 通讯作者:
    Linden,DavidR
{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

David R. Linden其他文献

Su1212 THE ELECTROGENIC SODIUM/BICARBONATE COTRANSPORTER SLC4A4 IS REQUIRED FOR SLOW WAVE (SW) GENERATION BY INTERSTITIAL CELLS OF CAJAL (ICC) BUT IS NOT SOLELY RESPONSIBLE FOR THE EFFECTS OF BICARBONATE ON SW ACTIVITY
  • DOI:
    10.1016/s0016-5085(24)02067-5
  • 发表时间:
    2024-05-18
  • 期刊:
  • 影响因子:
  • 作者:
    Natalie R. Wertish;Peter R. Strege;Siva Arumugam Saravanaperumal;Cheryl Bernard;Gianluca Cipriani;David R. Linden;Linda C. Hsi;Michael F. Romero;Gianrico Farrugia;Tamas Ordog
  • 通讯作者:
    Tamas Ordog
111 Altered P<sub>2</sub>X<sub>3</sub> Receptors in Prevertebral Ganglia During Colitis Is Dependent on Mammalian Target of Rapamycin
  • DOI:
    10.1016/s0016-5085(13)60091-8
  • 发表时间:
    2013-05-01
  • 期刊:
  • 影响因子:
  • 作者:
    David R. Linden
  • 通讯作者:
    David R. Linden
Su1236 TRP53-MEDIATED CELL CYCLE ARREST OF PRECURSORS RATHER THAN CELLULAR SENESCENCE UNDERLIES INTERSTITIAL CELL OF CAJAL DEPLETION DURING AGING
  • DOI:
    10.1016/s0016-5085(20)32084-9
  • 发表时间:
    2020-05-01
  • 期刊:
  • 影响因子:
  • 作者:
    Yujiro Hayashi;David R. Linden;Siva Arumugam Saravanaperumal;Yoshitaka Toyomasu;Simon J. Gibbons;Huihuang Yan;Gianrico Farrugia;Tamas Ordog
  • 通讯作者:
    Tamas Ordog
561 OPTOGENETIC STIMULATION OF INTESTINAL ENTEROENDOCRINE CELLS CAUSES EPITHELIAL CHLORIDE SECRETION THROUGH NEUROGENIC AND PARACRINE MECHANISMS
  • DOI:
    10.1016/s0016-5085(23)01202-7
  • 发表时间:
    2023-05-01
  • 期刊:
  • 影响因子:
  • 作者:
    Aura S. Ortegon Nino;Kaitlyn R. Knutson;Xi Yu;Halil S. Kacmaz;Anthony J. Treichel;Gianrico Farrugia;Arthur Beyder;David R. Linden
  • 通讯作者:
    David R. Linden
Mo2095 Distinct Expression Levels of Voltage-Gated Sodium Channels in Guinea Pig and Mouse Prevertebral Ganglion Neurons Are Unchanged During Colitis
  • DOI:
    10.1016/s0016-5085(13)62747-x
  • 发表时间:
    2013-05-01
  • 期刊:
  • 影响因子:
  • 作者:
    Ryan D. Peck;Elice M. Brooks;Gary M. Mawe;David R. Linden
  • 通讯作者:
    David R. Linden

David R. Linden的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('David R. Linden', 18)}}的其他基金

Mayo Clinic Research Education Program in Computational Autonomic Neurobiology of Diabetes and Digestive and Kidney Diseases
梅奥诊所糖尿病、消化和肾脏疾病计算自主神经生物学研究教育项目
  • 批准号:
    10709578
  • 财政年份:
    2022
  • 资助金额:
    $ 29.62万
  • 项目类别:
Neurobiology of Intrinsic Primary Afferent Neurons
内在初级传入神经元的神经生物学
  • 批准号:
    10477437
  • 财政年份:
    2021
  • 资助金额:
    $ 29.62万
  • 项目类别:
Neurobiology of Intrinsic Primary Afferent Neurons
内在初级传入神经元的神经生物学
  • 批准号:
    10680037
  • 财政年份:
    2021
  • 资助金额:
    $ 29.62万
  • 项目类别:
Neurobiology of Intrinsic Primary Afferent Neurons
内在初级传入神经元的神经生物学
  • 批准号:
    10654779
  • 财政年份:
    2021
  • 资助金额:
    $ 29.62万
  • 项目类别:
Neurobiology of Intrinsic Primary Afferent Neurons
内在初级传入神经元的神经生物学
  • 批准号:
    10275133
  • 财政年份:
    2021
  • 资助金额:
    $ 29.62万
  • 项目类别:
Neuroregeneration in the Enteric Nervous System
肠神经系统的神经再生
  • 批准号:
    8937180
  • 财政年份:
    2015
  • 资助金额:
    $ 29.62万
  • 项目类别:
Little Brain Big Brain Meeting
小脑大脑会议
  • 批准号:
    7745365
  • 财政年份:
    2009
  • 资助金额:
    $ 29.62万
  • 项目类别:
Extrinsic Neural Control of Gastrointestinal Function in the Disordered Bowel
肠道紊乱胃肠功能的外在神经控制
  • 批准号:
    8033223
  • 财政年份:
    2008
  • 资助金额:
    $ 29.62万
  • 项目类别:
Extrinsic Neural Control of Gastrointestinal Function in the Disordered Bowel
肠道紊乱胃肠功能的外在神经控制
  • 批准号:
    7595197
  • 财政年份:
    2008
  • 资助金额:
    $ 29.62万
  • 项目类别:
Myenteric Neuroplasticity Due to Experimental Colitis
实验性结肠炎引起的肌间神经可塑性
  • 批准号:
    6524630
  • 财政年份:
    2002
  • 资助金额:
    $ 29.62万
  • 项目类别:

相似海外基金

Spatiotemporal dynamics of acetylcholine activity in adaptive behaviors and response patterns
适应性行为和反应模式中乙酰胆碱活性的时空动态
  • 批准号:
    24K10485
  • 财政年份:
    2024
  • 资助金额:
    $ 29.62万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Structural studies into human muscle nicotinic acetylcholine receptors
人体肌肉烟碱乙酰胆碱受体的结构研究
  • 批准号:
    MR/Y012623/1
  • 财政年份:
    2024
  • 资助金额:
    $ 29.62万
  • 项目类别:
    Research Grant
CRCNS: Acetylcholine and state-dependent neural network reorganization
CRCNS:乙酰胆碱和状态依赖的神经网络重组
  • 批准号:
    10830050
  • 财政年份:
    2023
  • 资助金额:
    $ 29.62万
  • 项目类别:
Study on biological significance of acetylcholine and the content in food resources
乙酰胆碱的生物学意义及其在食物资源中的含量研究
  • 批准号:
    23K05090
  • 财政年份:
    2023
  • 资助金额:
    $ 29.62万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
alpha7 nicotinic acetylcholine receptor allosteric modulation and native structure
α7烟碱乙酰胆碱受体变构调节和天然结构
  • 批准号:
    10678472
  • 财政年份:
    2023
  • 资助金额:
    $ 29.62万
  • 项目类别:
Diurnal Variation in Acetylcholine Modulation of Dopamine Dynamics Following Chronic Cocaine Intake
慢性可卡因摄入后乙酰胆碱对多巴胺动力学调节的昼夜变化
  • 批准号:
    10679573
  • 财政年份:
    2023
  • 资助金额:
    $ 29.62万
  • 项目类别:
Differential Nicotinic Acetylcholine Receptor Modulation of Striatal Dopamine Release as a Mechanism Underlying Individual Differences in Drug Acquisition Rates
纹状体多巴胺释放的烟碱乙酰胆碱受体差异调节是药物获取率个体差异的机制
  • 批准号:
    10553611
  • 财政年份:
    2022
  • 资助金额:
    $ 29.62万
  • 项目类别:
Striatal Regulation of Cortical Acetylcholine Release
纹状体对皮质乙酰胆碱释放的调节
  • 批准号:
    10549320
  • 财政年份:
    2022
  • 资助金额:
    $ 29.62万
  • 项目类别:
Structural basis of nicotinic acetylcholine receptor gating and toxin inhibition
烟碱乙酰胆碱受体门控和毒素抑制的结构基础
  • 批准号:
    10848770
  • 财政年份:
    2022
  • 资助金额:
    $ 29.62万
  • 项目类别:
Mechanisms of nicotinic acetylcholine receptor modulation of cocaine reward
烟碱乙酰胆碱受体调节可卡因奖赏的机制
  • 批准号:
    10672207
  • 财政年份:
    2022
  • 资助金额:
    $ 29.62万
  • 项目类别:
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了