Neuroregeneration in the Enteric Nervous System

肠神经系统的神经再生

• 批准号: 8937180
• 负责人: David R. Linden
• 金额: $ 35.78万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 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
• 来源: https://reporter.nih.gov/project-details/8937180
• 关键词: Achalasia; Affect; Animal Model; Automobile Driving; Benzalkonium Chloride; Cells; Chagas Disease; Chronic; Congenital Megacolon; Constipation; Data; Digestive System Disorders; Disease; Dose; Enteral; Enteric Nervous System; Gastrointestinal tract structure; Gastroparesis; Genes; Genetic; Glial Fibrillary Acidic Protein; Goals; Growth; Homeobox; Human; Hybrids; In Vitro; Inflammatory Response; Injury; Intervention; Intestinal Pseudo-Obstruction; Intestines; Life; Mediating; Medical; Modeling; Molecular; Molecular Target; Mouse Strains; Mus; Myenteric Plexus; Natural regeneration; Nerve Regeneration; Neural Crest; Neural Crest Cell; Neuroglia; Neuronal Injury; Neurons; Neuropathy; Operative Surgical Procedures; Pathogenesis; Play; Proteins; RE1-silencing transcription factor; Repression; Signal Pathway; Small Intestines; Source; Stem cells; Structure; Symptoms; Testing; Therapeutic; Transgenic Mice; base; bone morphogenic protein; gliogenesis; insight; meetings; nerve supply; neuron loss; novel; novel therapeutic intervention; public health relevance; relating to nervous system; research study; therapy development; transcription factor; transdifferentiation

 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.

 描述（由申请人提供）：研究的总体目标是肠神经变成的机制，以发展针对肠神经病的内源性的派对。 ）Hirshsprung疾病，ACHARASIA和可能的慢速迁移构成，其特征是肠神经元的损害或丧失，即遗传症状症状。对于人类中的大多数神经病，其特征是严重的神经元丧失，通过神经rest前体依靠内源性神经再生。鼠小肠可诱导50％的神经元损失，并在体外菌株和稳定的肠道菌株接近肠神经元与SRY相关的同型转录因子2（SOX2）或总体假设，在两个特定的目标上，实验将确定新的新Neuring BAC的源和功能，因为目前尚不清楚细胞和植物的含量。从肠神经胶质的神经元和1.3个神经元具有功能性和多样化的神经元2将确定有助于肠神经变成的信号传导途径。神经基因。 对肠神经创造的机械理解，并为肠神经病的治疗方法提供了新的治疗方法的基础。