BLR&D Research Career Scientist Award Application

BLR

• 批准号: 10046730
• 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/10046730
• 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; Exposure to; Extramural Activities; Female; Foundations; Functional disorder; Funding; Future; Gastroenterology; Gastrointestinal tract structure; Gene Expression; Gene Targeting; Genes; Glucocorticoid Receptor; Goals; Grant; Gulf War veteran; HCN1 channel; Habits; Health; Healthcare; Hypersensitivity; Ileus; Industry; Industry Collaboration; Inflammatory Bowel Diseases; International; Interstitial Cystitis; Intestines; Investigational Therapies; Irritable Bowel Syndrome; Joints; Journals; Knowledge; Laboratories; Lead; Leadership; Life; Mediating; Methods; Military Personnel; Mission; Molecular; Neural Pathways; Neuraxis; Neuronal Plasticity; Neurons; Neuropharmacology; Neurosciences; Nociception; Oklahoma; Organ; Pain; Pathway interactions; Patient Care; Patients; Pharmacology; 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 Differences; Sexual abuse; Soldier; Solid; Stress; Symptoms; System; Techniques; United States Department of Veterans Affairs; 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; early life stress; editorial; experience; experimental study; gastrointestinal; graduate student; hypothalamic-pituitary-adrenal axis; improved; industry partner; innovation; insight; interest; knock-down; military veteran; neural circuit; neuropsychopharmacology; new therapeutic target; novel; novel therapeutics; pain sensitivity; 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).

项目概要/摘要 我的主要研究兴趣集中于中枢神经系统对内脏疼痛的调节 使用临床前啮齿动物模型和多种最先进的技术的目标，从分子和 细胞到行为、药理学和电生理学方法，以推进基础科学知识 这与患有内脏疼痛的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：弹性和新颖的机制 治疗：在我的研究的一方面，我们正在研究神经解剖学和神经药理学 内脏疼痛和焦虑之间相互作用的底物。我的研究重点是角色 杏仁核介导的内脏和躯体疼痛控制机制及其连接机制 焦虑和内脏（结肠）过敏。我们正在尝试识别至少一种潜在的神经元 可能参与内脏疼痛的中枢处理的底物。从那里我们希望确定一个 介导内脏疼痛中枢处理的神经基质内的受体机制。一个长期的 目标是研究神经基质如何在更大的神经网络内调节内脏疼痛敏感性 控制焦虑的途径，并利用这些知识来识别潜在的药物治疗靶点 介导内脏疼痛的中央处理通路。我们已经证明了长期持续的增长 对杏仁核局部暴露的反应的焦虑样行为和内脏敏感性 皮质酮（CORT）。我们发现 GR 表达持续下调，并且 CRF 和 HCN1 通道的表达导致 CeA 神经元过度兴奋。这些变化 基因表达代表了导致慢性焦虑和疼痛的潜在机制，通过促进 HPA 轴。最新实验的目标是利用基因敲低直接操纵CRF 和 GR 在中央杏仁核中表达。我们发现杏仁核内 CRF 的敲低会抑制 压力引起的慢性内脏和躯体疼痛，而杏仁核内 GR 的丧失是触发的关键 内脏和躯体疼痛。这些发现与基因靶向治疗的未来发展相关 治疗压力引起的内脏和躯体疼痛（由退伍军人事务部优异奖资助： 2013-2017）。 2. 成年后的早期生活压力导致内脏和躯体疼痛：性别差异。在女性中，IBS 最为严重 常见的胃肠道疾病。情绪压力、焦虑增加或单相和双相联想障碍经常发生 加剧症状。尽管有这些知识和证据表明女性与生活有着紧密的联系 压力源、身体/性虐待以及与爆发相关的情绪反应倾向 症状学方面，在增强我们对下行症状的理解方面几乎没有取得什么进展。 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 研究早期生活压力（ELS）环境影响伤害感受的机制 成年期。我们还在探索二次打击假说的证据，该假说是导致内脏疼痛脆弱性的基础 在女性中。具体来说，我们将研究早期生活中不可预测的压力导致的机制。 成年后出现慢性腹痛。此外，我们将评估 ELS 对杏仁核的影响 对成人压力源的反应（由退伍军人事务部优异奖资助：2010-2014；2015- 2019）。

项目成果

Environmental enrichment reverses stress-induced changes in the brain-gut axis to ameliorate chronic visceral and somatic hypersensitivity.

• DOI: 10.1016/j.ynstr.2023.100590
• 发表时间: 2024-01
• 期刊: NEUROBIOLOGY OF STRESS
• 影响因子: 5
• 作者: Orock, A.;Johnson, A. C.;Mohammadi, E.;Meerveld, B. Greenwood-Van
• 通讯作者: Meerveld, B. Greenwood-Van

Stress-Induced Chronic Visceral Pain of Gastrointestinal Origin.

• DOI: 10.3389/fnsys.2017.00086
• 发表时间: 2017
• 期刊: Frontiers in systems neuroscience
• 影响因子: 3
• 作者: Greenwood-Van Meerveld B;Johnson AC
• 通讯作者: Johnson AC

Reduced urothelial regeneration in rat bladders augmented with permeable porcine small intestinal submucosa assessed by magnetic resonance imaging.

• DOI: 10.1002/jbm.b.33985
• 发表时间: 2018-07
• 期刊: Journal of biomedical materials research. Part B, Applied biomaterials
• 作者: Qing Yang;D. Xia;R. Towner;N. Smith;D. Saunders;K. Fung;C. Aston;B. Greenwood-Van Meerveld;R. Hurst;S. Madihally;B. Kropp;Hsueh-Kung Lin

Targeting epigenetic mechanisms for chronic visceral pain: A valid approach for the development of novel therapeutics.

• DOI: 10.1111/nmo.13500
• 发表时间: 2019-03
• 期刊: Neurogastroenterology and motility
• 影响因子: 3.5
• 作者: Louwies T;Ligon CO;Johnson AC;Greenwood-Van Meerveld B
• 通讯作者: Greenwood-Van Meerveld B

Stereotaxic Exposure of the Central Nucleus of the Amygdala to Corticosterone Increases Colonic Permeability and Reduces Nerve-Mediated Active Ion Transport in Rats.

• DOI: 10.3389/fnins.2018.00543
• 发表时间: 2018
• 期刊: Frontiers in neuroscience
• 影响因子: 4.3
• 作者: Hattay P;Prusator DK;Johnson AC;Greenwood-Van Meerveld B
• 通讯作者: Greenwood-Van Meerveld B