BLR&D Research Career Scientist Award Application

BLR

• 批准号: 9231123
• 负责人: Beverley Greenwood-Van Meerveld
• 金额: --
• 依托单位: OKLAHOMA CITY VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-10-01 至 2023-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9231123
• 关键词: Abdominal Pain; Address; Adult; Adverse effects; Affect; American; Amygdaloid structure; Anxiety; Area; Award; Basic Science; Biology; Brain; Caring; Chronic; Clinical Sciences; Communication; Contracts; Corticosterone; Corticotropin-Releasing Hormone; Development; Diagnosis; Digestive System Disorders; Disease; Disease Outbreaks; Down-Regulation; Electrophysiology (science); Emotional; Exhibits; Extramural Activities; Female; Foundations; Functional disorder; Funding; Future; Gastroenterology; Gastrointestinal tract structure; Gene Expression; Gene Targeting; Genes; Glucocorticoid Receptor; Goals; Grant; Gulf War; HCN1 channel; Habits; Health; Hypersensitivity; Ileus; Industry; Industry Collaboration; Inflammatory Bowel Diseases; International; Interstitial Cystitis; Intestines; Investigational Therapies; Irritable Bowel Syndrome; Joints; Journals; Knowledge; Laboratories; Lead; Leadership; Life; Life Stress; Mediating; Methods; Military Personnel; Mission; Molecular; Neural Pathways; Neuraxis; Neuronal Plasticity; Neurons; Neuropharmacology; Neurosciences; Nociception; Oklahoma; Organ; Pain; Pathway interactions; Patient Care; Patients; Pharmacology; Population; Postdoctoral Fellow; Postoperative Period; Predisposition; Presbyterian Church; Privatization; Psychiatry; Publications; Reagent; Recording of previous events; Regulation; Reporting; Research; Research Project Grants; Risk; Risk Factors; Rodent Model; Role; Scientific Advances and Accomplishments; Scientist; Services; Sex Characteristics; Sexual abuse; Soldier; Solid; Stress; Symptoms; Syndrome; System; Techniques; United States National Institutes of Health; Universities; Veterans; Visceral; Visceral pain; Woman; anxiety-like behavior; authority; behavioral pharmacology; career; cell motility; chronic abdominal pain; combat; design; editorial; experience; experimental study; gastrointestinal; graduate student; improved; industry partner; innovation; insight; interest; knock-down; neural circuit; neuropsychopharmacology; new therapeutic target; novel; novel therapeutics; pre-clinical; programs; receptor; receptor expression; relating to nervous system; research and development; research study; resilience; response; stressor; symptomatology; targeted treatment; undergraduate student

Project Summary/Abstract My primary research interest focuses on the central nervous system regulation of visceral pain with a strategic objective of using preclinical rodent models and multiple state-of-the-art techniques, from molecular and cellular to behavioral, pharmacological and electrophysiological methods to advance basic scientific knowledge that has direct relevance to the diagnosis and treatment of veterans with visceral pain. Below I have summarized the main research projects in my laboratory. 1. Central Neural Circuitry Underlying Anxiety and Visceral pain: Mechanisms of Resilience and Novel Treatments: In one aspect of my research we are studying the neuroanatomical and neuropharmacological substrates involved in the interaction between visceral pain and anxiety. My research focuses on the role of amygdala-mediated mechanisms in the control of visceral and somatic pain and the mechanisms connecting anxiety and visceral (colonic) hypersensitivity. We are attempting to identify at least one potential neural substrate that might be involved in the central processing of visceral pain. From there we hope to identify a receptor mechanism within the neural substrate that mediates central processing of visceral pain. A long-term goal is to investigate how the neural substrate modulates visceral pain sensitivity within the larger neural pathway controlling anxiety, and use this knowledge to identify potential pharmacotherapeutic targets in the central processing pathway that mediates visceral pain. We have demonstrated long lasting increases in anxiety-like behavior and viscerosomatic sensitivity in response to the local exposure of the amygdala to corticosterone (CORT). We found persistent down-regulation of GR expression and increases in the expression of CRF and HCN1 channels leading to hyper-excitability of the CeA neurons. These changes in gene expression represent a potential mechanism leading to chronic anxiety and pain, via facilitation of the HPA axis. The objective of latest experiments has been to use gene knockdown to directly manipulate CRF and GR expression in the central amygdala. We found that knockdown of CRF within the amygdala inhibits stress-induced chronic visceral and somatic pain, and that loss of GR within the amygdala is key to triggering visceral and somatic pain. Such findings are relevant for the future development of gene targeted therapeutics to treat stress-induced visceral and somatic pain (Funded by the Department of Veteran's Affairs Merit Award: 2013-2017). 2. Early life stress on visceral and somatic pain in adulthood: Sex differences. In women, IBS is the most prevalent GI disorders. Emotional stressors, increased anxiety or uni- and bipolar associative disorders often exacerbate symptoms. Despite this knowledge and evidence that females embody strong connections to life stressors, physical/sexual abuse and an emotionally reactive disposition related to the outbreak of symptomatology, there has been very little progress made to enhance our understanding of the descending connections between the brain and the GI tract in female Veterans. Our latest project was designed to investigate the mechanisms by which the context of the early life stress (ELS) can affect nociception in adulthood. We are also exploring evidence for a two hit hypothesis underlying the vulnerability to visceral pain in females. Specifically, we will investigate the mechanisms by which an unpredictable stress in early life leads to chronic abdominal pain in adulthood. Additionally we will assess the impact of ELS on the amygdala response to an adult stressor (Funded by the Department of Veteran's Affairs Merit Award: 2010-2014; 2015- 2019).

项目摘要/摘要 我的主要研究兴趣集中在中枢神经系统对内脏痛的调节上 目的利用临床前啮齿动物模型和多种最先进的技术，从分子和 从细胞到行为、药理学和电生理学的方法，以促进基本的科学知识 这与内脏疼痛退伍军人的诊断和治疗有直接关系。下面我有 总结了我实验室的主要研究项目。 1.焦虑和内脏疼痛背后的中枢神经回路：弹性机制和新发现 治疗：在我的研究的一个方面，我们正在研究神经解剖学和神经药理学 参与内脏疼痛和焦虑相互作用的底物。我的研究重点是 杏仁核介导的内脏和躯体疼痛控制机制及其联系机制 焦虑和内脏(结肠)过敏。我们正在尝试识别至少一个潜在的神经 可能参与内脏痛的中枢处理的底物。从那里我们希望确定一个 神经底物中的受体机制，调节内脏痛的中枢处理。一个长期的 目的是研究神经基质如何在较大的神经细胞内调节内脏疼痛敏感性。 控制焦虑的途径，并使用这一知识来确定潜在的药物治疗靶点 调节内脏疼痛的中央处理通路。我们已经展示了长期持续的增长 杏仁核局部暴露对焦虑样行为和内脏敏感性的影响 皮质酮(CORT)。我们发现GR表达持续下调，而 CRF和HCN1通道的表达导致CEA神经元的高兴奋性。这些变化在 基因表达是导致慢性焦虑和疼痛的潜在机制，通过促进 百帕轴线。最新实验的目标是利用基因敲除来直接操纵慢性肾衰 杏仁中央核有GR表达。我们发现，杏仁核中CRF的敲除抑制了 应激诱导慢性内脏和躯体疼痛，杏仁核内GR的丢失是触发 内脏和躯体疼痛。这些发现与基因靶向治疗的未来发展有关。 治疗应激引起的内脏和躯体疼痛(退伍军人事务部荣誉奖资助： 2013-2017年)。 2.成年早期生活压力对内脏和躯体疼痛的影响：性别差异。在女性中，IBS是最多的 普遍存在的胃肠道疾病。情绪压力源、焦虑增加或单、双相关联障碍通常 加重症状。尽管有这些知识和证据表明女性与生命有很强的联系 与暴发有关的压力源、身体/性虐待和情绪反应倾向 症状学方面，在加强我们对下降的了解方面进展甚微。 女性退伍军人大脑和胃肠道之间的联系。我们最新的项目旨在 探讨早期生活应激(ELS)环境影响大鼠伤害性感受的机制 成人期。我们还在探索内脏疼痛易感性的两次命中假说的证据。 在雌性身上。具体地说，我们将研究早期生活中不可预测的压力导致的机制 到成年后的慢性腹痛。此外，我们还将评估ELS对杏仁核的影响 对成人应激源的反应(由退伍军人事务部资助：2010-2014；2015- 2019年)。