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Central Molecular Mechanisms of Stress-Induced Visceral Hypersensitivity

压力诱发内脏超敏反应的中心分子机制

基本信息

批准号：
8329013
负责人：
Anthony Christopher Johnson
金额：
$ 2.62万
依托单位：
UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-30 至 2013-09-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8329013
关键词：
Abdominal Pain Address Adrenal Cortex Hormones Affect Amygdaloid structure Animal Model Animals Anxiety Anxiety Disorders Applications Grants Area Behavioral Biological Markers Brain CRF receptor type 1 Cell Nucleus Chronic Clinical Clinical Research Complement Corticosterone Corticotropin-Releasing Hormone Data Development Disease Down-Regulation Etiology Exhibits Fibromyalgia Functional Gastrointestinal Disorders Future Gastrointestinal Process Gene Expression Genes Genomics Glucocorticoid Receptor Glucocorticoids Habits Hormones Hyperalgesia Hypersensitivity Hypothalamic structure Immune Immunohistochemistry In Situ Hybridization Incidence Intestines Irritable Bowel Syndrome Lead Literature Measures Mediating Mentors Mineralocorticoid Receptor Modeling Molecular Monitor Neuraxis Neurosciences Neurotransmitters Pain Patients Pharmaceutical Preparations Polymerase Chain Reaction Pre-Clinical Model Rattus Receptor Signaling Regulation Reporting Risk Rodent Rodent Model Role Series Signal Pathway Signal Transduction Stress Structure Symptoms Techniques Time Training Treatment Efficacy United States National Institutes of Health Veterans Visceral Visceral pain Water Western Blotting Work base behavior measurement central sensitization direct application experience gastrointestinal graduate student improved insight knock-down new therapeutic target novel patient population prevent primary outcome protein expression public health relevance receptor receptor expression research study response tool

项目摘要

DESCRIPTION (provided by applicant): The hallmark symptom of irritable bowel syndrome (IBS), a chronic functional gastrointestinal (GI) disorder, is severe abdominal pain, associated with altered bowel habits, in the absence of any identifiable disease. While the cause of IBS is unknown, clinical evidence suggests a relationship between abdominal pain and stress and anxiety, suggesting a change in the brain's processing of GI signals in these patients. Using pre- clinical models, we have previously demonstrated that activation of the amygdala, an area of the brain that regulates stress and anxiety and has been identified in clinical studies, can induce anxiety and GI pain/hypersensitivity in the rat. Additionally in this animal model with IBS-like symptomatology, we then demonstrated that treating the rodents with drugs that prevented the effects of stress hormones reversed the anxiety and pain. While we have gained some insights into how the brain regulates hypersensitivity in this model, what remains unknown is "Which genes in the amygdala regulate anxiety and GI pain?" To address this question, this project will use two specific aims: 1) Investigate how stress hormone expression in the amygdala changes in an animal with induced-anxiety and GI hypersensitivity. In this aim, we will monitor both gene and protein expression in two complementary animal models, to determine which genes are responsible for the IBS-like symptoms. 2) Determine if blocking the changes in stress hormones in the amygdala prevents the development of anxiety and GI pain. In this aim, by preventing the increased gene expression in our models at the level of the amygdala, we will provide additional evidence for a central role in the co-regulation of GI hypersensitivity and anxiety. To achieve these specific aims, the mentor, Dr. Greenwood-Van Meerveld, has assembled a team of experienced collaborators to provide the trainee, Mr. Anthony C. Johnson, with the necessary tools to perform the molecular techniques necessary to monitor both total (quantitative reverse polymerase chain reaction, western blotting) and localized (in situ hybridization, immunohistochemistry) gene and protein expression. These molecular techniques will complement the training that she has provided on the behavioral measurements of anxiety and pain in IBS-like animal models. Successful completion of the experiments proposed in this project will provide additional evidence for the molecular mechanisms of stress-induced colonic hypersensitivity, providing new therapeutic targets for the treatment of IBS. PUBLIC HEALTH RELEVANCE: Successful completion of the aims proposed within this application will provide evidence for the role of the amygdala in the development of colonic hypersensitivity in rats and will offer new insights into the molecular mechanisms of central sensitization that likely lead to chronic symptomatology in the irritable bowel syndrome patient population. More importantly, our findings may identify novel targets for new therapies directed at visceral pain to improve the treatment or even reduce the risk for the development of irritable bowel syndrome.

描述（由申请人提供）：肠易激综合征（IBS）是一种慢性功能性胃肠道（GI）疾病，在没有任何可识别疾病的情况下，其标志性症状是严重腹痛，与排便习惯改变相关。虽然肠易激综合征的病因尚不清楚，但临床证据表明，腹痛与压力和焦虑之间存在联系，这表明这些患者大脑处理胃肠道信号的方式发生了变化。使用临床前模型，我们之前已经证明，杏仁核（大脑中调节压力和焦虑的区域，并已在临床研究中确定）的激活可以诱导大鼠的焦虑和胃肠道疼痛/过敏。此外，在这个具有ibs样症状的动物模型中，我们随后证明，用药物治疗啮齿动物，阻止应激激素的作用，逆转了焦虑和疼痛。虽然我们在这个模型中对大脑如何调节超敏反应有了一些了解，但仍然未知的是“杏仁核中的哪些基因调节焦虑和胃肠道疼痛？”为了解决这个问题，本项目将有两个具体目标：1)研究应激激素在诱发性焦虑和胃肠道过敏的动物杏仁核中的表达如何变化。为此，我们将在两个互补的动物模型中监测基因和蛋白质的表达，以确定哪些基因负责ibs样症状。2)确定阻断杏仁核中应激激素的变化是否可以防止焦虑和胃肠道疼痛的发展。为此，通过在我们的模型中防止杏仁核水平的基因表达增加，我们将为GI过敏和焦虑的共同调节中的核心作用提供额外的证据。为了实现这些具体目标，导师Greenwood-Van Meerveld博士召集了一个经验丰富的合作者团队，为实习生Anthony C. Johnson先生提供必要的工具，以执行必要的分子技术来监测总（定量反向聚合酶链反应，western blotting）和局部（原位杂交，免疫组织化学）基因和蛋白质表达。这些分子技术将补充她在ibs类动物模型中提供的焦虑和疼痛行为测量方面的培训。本课题实验的成功完成将为应激性结肠超敏反应的分子机制提供进一步的证据，为IBS的治疗提供新的治疗靶点。