Mechanisms of Postoperative Ileus

术后肠梗阻的机制

基本信息

批准号：
7688268
负责人：
YVETTE FRANCE TACHE
金额：
--
依托单位：
VA GREATER LOS ANGELES HEALTHCARE SYSTEM
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-04-01 至 2013-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7688268
关键词：
Abdomen Abdominal Pain Affinity Agonist Analgesics Anti-Inflammatory Agents Anti-inflammatory Area Autonomic nervous system Brain Brain Stem CRF receptor type 1 CRF receptor type 2 Cell Nucleus Cerebral Ventricles Chewing Gum Colon Conscious Corticotropin-Releasing Hormone Corticotropin-Releasing Hormone Receptors Data Development Disease Excision Experimental Models Gastrointestinal Motility Gastroparesis Gene Expression Grant Health Care Costs Hospitals Hypothalamic structure Ileus Immune Immunohistochemistry Impairment Incidence Inflammation Inflammatory Inflammatory Response Injection of therapeutic agent Injury Intestines Intravenous Laboratories Laparotomy Lasers Lateral Ligands Link Liquid substance Malignant Neoplasms Medical Research Meta-Analysis Methods Mission Modality Molecular Probes Monitor Motor Nausea Neurons Nitric Oxide Nitric Oxide Synthase Type I Operative Surgical Procedures Opiates Opioid Receptor Outcome Palpation Pathogenesis Pathway interactions Patient Care Patients Peptides Peripheral Pharmaceutical Preparations Pharmacology Play Polymerase Chain Reaction Pontine structure Postoperative Period Preventive Process Progress Reports Protein Isoforms RNA Splicing Rattus Recovery Recruitment Activity Regulation Research Research Priority Resolution Reverse Transcriptase Polymerase Chain Reaction Rodent Role Signal Pathway Signal Transduction Small Intestines Stomach Stress System Testing Therapeutic Intervention Thyrotropin-Releasing Hormone Time Transgenic Mice Trauma United States Up-Regulation Vagus nerve structure Variant Veterans Vomiting War Work arm bariatric surgery base cell motility cholinergic combat corticotropin releasing factor-binding protein gastrointestinal system hormone analog improved insight interest laser capture microdissection macrophage motility disorder mouse model nerve supply novel novel strategies pressure psychological stressor public health relevance receptor research study response sensor sham feeding somatostatin analog stressor tool urocortin

项目摘要

DESCRIPTION (provided by applicant): ABSTRACT The long-term objective is to open new strategies to reduce the development of postoperative ileus (POI) occurring after abdominal surgery involving manipulation of the bowel by increasing the understanding of neuro-immune mechanisms in rodent experimental models of POI. Besides causing significant discomfort to patients (bloating, nausea, emesis, and abdominal pain), POI hampers recovery and constitutes the most common reason for delaying discharge from the hospital after surgery, thus incurring a substantial socio- economical burden. Recent reviews of treatment modalities point out the lack of efficient preventive therapy and our poor understanding of pathophysiological mechanisms. We will test the hypothesis, based on data obtained during the last granting period and novel preliminary data, that abdominal surgery recruits stress- related mechanisms, most prominently corticotropin releasing factor (CRF) receptor 2 (CRF2) system in the brain and the gut, which contributes to orchestrate alterations in extrinsic and myenteric neuronal activity and local inflammatory response leading to impairment of gut propulsive motor function. This will be achieved by 1) characterizing the expression of CRF ligands (CRF and urocortins, Ucns), CRF receptors and their splice variants at selective brain nuclei regulating autonomic outflow to the colon and establishing the functional relevance of brain CRF2 receptors in colonic POI using pharmacological approach; 2) assessing the up- regulation of Ucns/CRF2 system within the colon and related increased release of nitric oxide from neurons and resident macrophages, thereby decreasing colonic motility; 3) establishing that activation of brain CRF pathways in response to abdominal surgery induces stimulation of sympathetic outflow and inhibition of vagal activity and counteracting these autonomic changes improves POI by restoring myenteric neuronal activity and curtailing the local inflammatory response. The approaches to achieve these aims will dwell on new technical advances recently made in our laboratories including key molecular probes to assess gene expression of rodent CRF ligands and CRF1 and CRF2 receptors and novel receptor variants that we have cloned, the use of laser captured microdissected brain nuclei, the ability to monitor increase in neuronal activity in the brain and myenteric neurons using functional Fos immunohistochemistry along with real-time monitoring of colonic motility with novel non-invasive methods of Mikrotip pressure sensor in conscious rodents, pharmacological tools (selective CRF receptor subtype agonists and antagonists) and transgenic mouse models . The characterization of CRF/Ucns signaling pathways in the brain and the gut that contribute to POI induced by abdominal surgery will enable us to uncover novel mechanisms in the pathogenesis of POI. This experimental research is relevant to the VA patient care mission as part of the medical research priority area that relates to stress, trauma and disorders of the gastrointestinal system, which is particularly pertinent as an increasing number of combat veterans deployed in war zone suffered traumatic injuries that required surgery. PUBLIC HEALTH RELEVANCE: NARRATIVE This research directed to uncover mechanisms underlying the pathogenesis of postoperative ileus linked with abdominal surgery is relevant to the patient care mission as part of the medical research priority area that relates to stress, trauma and disorders of the gastrointestinal system, which is particularly pertinent as a number of veterans deployed in war zone undergo injuries requiring surgery and the high incidence of veterans undergoing abdominal surgery for removal of malignancies, bariatric surgery or other conditions.

描述（由申请人提供）：摘要的长期目标是开放新的策略，以减少腹部手术后发生的术后发育（POI）的发展，涉及对肠道操纵的肠道操纵，通过增加对POI啮齿动物实验模型中神经免疫机制的理解。除了给患者带来严重的不适（腹胀，恶心，呕吐和腹痛）外，POI会阻碍恢复，构成了手术后延迟从医院出院的最常见原因，从而造成了实质性的社会经济负担。最近对治疗方式的评论指出，缺乏有效的预防疗法以及我们对病理生理机制的不良理解。我们将根据在上次批准期间获得的数据和新的初步数据测试假设，即腹部手术招募了与压力相关的机制，最突出的是皮质激素释放因子（CRF）受体2（CRF）受体2（CRF2）在大脑和肠中的系统，这有助于局部范围内的范围内的局部疗效，并有助于界面范围，并有助于界面的促进性，并有助于外层的脉络脉络性，并有助于外部脉络脉络性造成脉络性的影响。运动功能。这将通过1）表征CRF配体（CRF和UROCORTIS，UCN），CRF受体及其在选择性脑核的剪接变体的表达来实现，从而调节对结肠自主流出并确定脑CRF2受体在结肠POI中使用药物学方法中的脑CRF2受体的功能相关性； 2）评估结肠内UCN/CRF2系统的上调节，并相关的一氧化氮从神经元和常驻巨噬细胞中释放，从而降低了结肠运动； 3）确定脑CRF途径响应腹部手术的激活会引起交感神经流出和抑制迷走神经活动的刺激，并抵消这些自主神经变化，从而通过恢复脑膜神经元活性并减少局部炎症反应来改善POI。实现这些目标的方法将停留在我们实验室最近在我们的实验室中取得的新技术进步，包括关键分子探针，以评估啮齿动物CRF配体和CRF1和CRF2和CRF2受体的基因表达，以及我们已克隆的新型受体变异，使用激光捕获的微型脑核的功能增加了激光捕获的脑核中的脑和脑膜化的能力，这种功能会增加脑膜和脑膜的功能，并增加神经元素的活性。在有意识的啮齿动物中的Mikrotip压力传感器，药理学工具（选择性CRF受体亚型激动剂和拮抗剂）和转基因小鼠模型中，使用新型的Mikrotip压力传感器对结肠运动的实时监测。 CRF/UCNS信号通路的表征以及腹部手术引起的POI的肠道表征将使我们能够在POI发病机理中发现新的机制。这项实验研究与VA患者护理任务有关，这是与胃肠道系统的压力，创伤和疾病有关的医学研究优先领域的一部分，这在战区中部署在战区中的越来越多的战斗退伍军人遭受了需要手术的创伤性伤害。公共卫生相关性：叙事这项研究针对揭示与腹部手术有关的术后发病机制的基础机制，与患者护理任务是医学研究优先区域的一部分，与胃肠道系统的压力，创伤和疾病有关，这是胃肠道系统的疾病，这在遭受了远程繁忙的狂热范围内，这与遭受了繁重的侵害，这是遭受狂热的繁忙范围。用于去除恶性肿瘤，减肥手术或其他情况。