Neuroregeneration in the Enteric Nervous System

肠神经系统的神经再生

基本信息

  • 批准号:
    8937180
  • 负责人:
  • 金额:
    $ 35.78万
  • 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:
    2015-08-15 至 2018-04-30
  • 项目状态:
    已结题

项目摘要

 DESCRIPTION (provided by applicant): The overall goal of these studies is to understand the mechanisms of enteric neuroregeneration in order to develop therapies targeted toward endogenous repopulation of the enteric nervous system (ENS) for the treatment of enteric neuropathy. Enteric neuropathy, which contribute to numerous digestive diseases including idiopathic gastroparesis, chronic intestinal pseudoobstruction (CIPO) Hirshsprung's disease, Chagas' disease, achalasia, and possibly slow transit constipation, are characterized by damage or loss of enteric neurons. Existing animal models of enteric neuropathy, i.e., genetic aganglionosis are characterized by complete loss of neural crest cells including neurons and glia. This complete loss, while recapitulating severe congenital human enteric neuropathy, is in contrast to most enteric neuropathy in humans, which are characterized by less severe neuronal loss, and importantly essentially precludes endogenous neural regeneration by neural crest precursors. Overcoming this limitation, we developed a novel low-dose, instead of the traditional high-dose, benzalkonium chloride (BAC) model in the murine small intestine to induce a loss of 50% of neurons, and robust neuroregeneration. It is the only animal model to date that demonstrates robust endogenous neuroregeneration. Using this model with novel transgenic mouse strains and additional in vitro approaches, we will test the overall hypothesis that regeneration of the myenteric plexus is mediated by transdifferentiation of enteric glia to neurons via a SRY-related homeobox transcription factor 2 (SOX2)- dependent mechanism. Our overall hypothesis will be tested by experiments directed at two specific aims. Specific Aim 1 will determine the source and functionality of new neurons following BAC treatment because currently, the cellular origin and function of regenerating neurons are not understood. This aim will be met by testing three hypotheses: 1.1) new neurons derive from enteric cells that express glial fibrillary acidic protein (GFAP); 1.2) glia directly transdifferentiate into neurons; and 1.3 neurons derived from enteric glia are functional and diverse. Enteric glia as a manipulable endogenous source of enteric neurons would be a significant advance because glia outnumber neurons 4:1 in the ENS and are continually replenished by constitutive gliogenesis. Specific Aim 2 will determine the signaling pathways that contribute to enteric neuroregeneration. This aim will be met by testing three hypotheses: 2.1) SOX2 expression in glia is necessary and sufficient to generate new neurons; 2.2) bone morphogenic protein 2 (BMP2) induces SOX2 expression in enteric glial cells; and 2.3) SOX2 reprograms enteric glia to neurons by removing RE1-silencing transcription factor (REST)-mediated repression of neural genes. Results of the proposed studies, involving morphological and molecular characterization of novel transgenic mouse strains for genetic lineage tracing, clonal analysis, and molecular targeting, will provide a mechanistic understanding of enteric neuroregeneration and provide the basis for novel therapeutic approaches for the treatment of enteric neuropathy.


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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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
671 MECHANOSENSITIVE ENTEROENDOCRINE CELLS REGULATE FORCE-INDUCED EPITHELIAL SECRETION
  • DOI:
    10.1016/s0016-5085(21)01065-9
  • 发表时间:
    2021-05-01
  • 期刊:
  • 影响因子:
  • 作者:
    Isabelle W. Finholm;Anthony J. Treichel;Kaitlyn R. Knutson;Madhusudan Grover;David R. Linden;Andrew B. Leiter;Gianrico Farrugia;Arthur Beyder
  • 通讯作者:
    Arthur Beyder

David R. Linden的其他文献

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{{ 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:
    $ 35.78万
  • 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:
    $ 35.78万
  • 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:
    $ 35.78万
  • 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:
    $ 35.78万
  • 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:
    $ 35.78万
  • 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:
    $ 35.78万
  • 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:
    $ 35.78万
  • 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:
    8217087
  • 财政年份:
    2008
  • 资助金额:
    $ 35.78万
  • 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:
    $ 35.78万
  • 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:
    $ 35.78万
  • 项目类别:

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