Central Neuropeptide Y (NPY): A Novel Target for PTSD Pathophysiology

中枢神经肽 Y (NPY)：PTSD 病理生理学的新靶点

• 批准号: 8253506
• 负责人: RENU SAH
• 金额: --
• 依托单位: CINCINNATI VA MEDICAL CENTER RESEARCH
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8253506
• 关键词: Address; Amygdaloid structure; Animal Model; Animals; Anxiety; Anxiety Disorders; Behavior; Behavioral; Biological Markers; Biological Psychiatry; Brain; Cardiovascular system; Cerebrospinal Fluid; Chronic; Chronic stress; Clinical; Clinical Research; Collaborations; Control Groups; Data; Development; Diagnosis; Diamond; Emotional Stress; Enzyme Immunoassay; Event; Exposure to; Fright; Functional disorder; Goals; Grant; High Prevalence; Hormones; Human; Immunohistochemistry; In Situ Hybridization; Individual; Intervention; Knowledge; Lead; Link; Measures; Memory; Neurobiology; Neurons; Neuropeptide Y Receptor; Outcome; Patient Care; Patients; Pharmacology; Pharmacotherapy; Phenotype; Physiological; Physiology; Post-Traumatic Stress Disorders; Pre-Clinical Model; Predisposition; Prevalence; Prevention; Recovery; Regulation; Reporting; Research; Resistance; Rodent; Rodent Model; Role; Screening procedure; Signal Transduction; Simulate; Stress; Supplementation; System; Testing; Therapeutic; Therapeutic Intervention; Trauma; Trauma recovery; Veterans; War; Work; analog; base; biological adaptation to stress; body system; combat; coping; effective intervention; experience; improved; interest; mRNA Expression; neuropeptide Y; novel; operation; pre-clinical; preclinical study; protein expression; public health relevance; receptor binding; resilience; response; stress resilience; translational study

DESCRIPTION (provided by applicant): Post-Traumatic Stress Disorder (PTSD) is a chronic and disabling condition that can occur in individuals who experience a traumatic event. Given the rising prevalence of PTSD, especially combat related, studies on the search for novel, effective interventions and preclinical models relevant to PTSD are currently a high priority. Poor post-trauma recovery and susceptibility to PTSD is an outcome of impaired resilience and coping to stress. Abnormalities in the stress regulatory systems of the body are also found in PTSD. Neuropeptide Y (NPY) is a major transmitter that is linked to the regulation of stress and anxiety, and has been recognized as a "stress resilience factor" in humans and rodents. In recent studies, we have reported low cerebrospinal fluid concentrations of NPY in veterans with PTSD. The physiological and therapeutic relevance of NPY to PTSD is of high interest but remains to be investigated. This Merit Review application proposes to investigate NPY in a preclinical rodent model of PTSD to gain physiological and therapeutic relevance of NPY to PTSD. Importantly, therapeutic potential of NPY and novel, brain permeant NPY analogs will also be screened for recovery outcomes following trauma. The rodent model of chronic variable stress (CVS) simulates the unpredictability, chronicity and lack of control of combat- associated trauma and invokes the expression of PTSD-like behaviors/physiology. Importantly, our data has shown a persistent CVS-evoked deficit of NPY in the amygdala (a region dysregulated in individuals with PTSD). The central hypothesis of this application is that deficiency of amygdalar NPY promotes the expression of anxiety, exaggerated fear-memory (re-experiencing), startle (hyperarousal) and sympathetic overdrive; and that supplementation of NPY or peripherally injected NPY analogs will promote resistance/resilience to CVS induced deficits. Three specific aims will investigate these hypotheses: Aim 1 will test the hypothesis that exposure to CVS will lead to delayed and persistent dysregulation of amygdalar NPY system, Aim 2 will test the hypothesis that deficits in amygdalar NPY prior to CVS trauma will exacerbate behavioral and physiological deficits evoked by CVS trauma Aim 3 will test the hypothesis that supplementation of amygdalar NPY or NPY-Y2 antagonists is sufficient to induce resistance/resilience to late- emerging chronic stress-induced behavioral deficits. Collectively, our data will determine the physiologic and potential therapeutic relevance of NPY in PTSD. Relevance: This preclinical study will provide the rationale to proceed with the development of NPY analogs for PTSD pharmacotherapy and as a potential biomarker for predicting trauma outcomes. PUBLIC HEALTH RELEVANCE: Studies have reported a high prevalence of PTSD (23%) among deployed veterans from recent wars. Significant gaps remain in our understanding of PTSD neurobiology, prevention, and effective therapeutic interventions. Much of our knowledge about PTSD has been generated from preclinical models and translational studies. This Merit review application focuses on Neuropeptide Y (NPY), a stress resiliency hormone in humans. In recent collaborations with the Cincinnati VA, the PI has reported reduced levels of NPY in combat veterans with PTSD (Sah et al Biological Psychiatry 2009). The current proposal uses a preclinical rodent model of PTSD to understand the physiological and therapeutic relevance of NPY to PTSD. Impact on Patient Care: The goal of this research is to identify NPY as a potential target of intervention and a predictive biomarker to screen for trauma outcomes. Findings will provide the rationale to initiate clinical studies on NPY screening and supplementation to aid in PTSD diagnosis and improved treatment in veterans.

描述(由申请人提供)： 创伤后应激障碍(PTSD)是一种慢性致残性疾病，可发生在经历创伤事件的个人中。鉴于创伤后应激障碍的患病率不断上升，尤其是与战斗相关的，寻找与创伤后应激障碍相关的新的、有效的干预措施和临床前模式的研究目前是当务之急。创伤后恢复差和对创伤后应激障碍的敏感性是复原力受损和应对压力的结果。创伤后应激障碍患者体内的压力调节系统也会出现异常。神经肽Y(NPY)是调节应激和焦虑的主要递质，在人类和啮齿动物中被认为是一种“应激恢复因子”。在最近的研究中，我们报告了患有创伤后应激障碍的退伍军人脑脊液中NPY浓度较低。NPY与创伤后应激障碍的生理和治疗相关性引起了人们的高度关注，但仍有待研究。这个Merit Review应用程序建议在PTSD的临床前啮齿动物模型中研究NPY，以获得NPY与PTSD的生理和治疗相关性。重要的是，NPY和新奇的脑部NPY类似物的治疗潜力也将被筛选出来，以了解创伤后的康复结果。慢性可变应激(CVS)啮齿动物模型模拟了战斗相关创伤的不可预测性、长期性和缺乏控制性，并调用了创伤后应激障碍样行为/生理的表达。重要的是，我们的数据显示，CVS诱发的杏仁核(创伤后应激障碍患者的一个区域)NPY持续缺乏。这一应用的中心假设是，杏仁核NPY缺乏促进焦虑、夸张的恐惧记忆(重新体验)、惊吓(高度唤醒)和交感过度驱动的表达；补充NPY或外周注射NPY类似物将促进对CVS诱导的缺陷的抵抗/弹性。三个特定的目标将研究这些假说：目标1将测试假设，暴露于CVS将导致杏仁核NPY系统延迟和持续的失调，目标2将测试假设，即在CVS创伤之前杏仁核NPY的缺陷将加剧由CVS创伤引起的行为和生理缺陷。目标3将测试补充杏仁核NPY或NPY-Y2拮抗剂足以诱导对后期出现的慢性应激诱导的行为缺陷的抵抗/弹性的假设。总的来说，我们的数据将确定NPY在创伤后应激障碍中的生理学和潜在的治疗相关性。相关性：这项临床前研究将提供继续开发NPY类似物用于创伤后应激障碍药物治疗的理论基础，并将其作为预测创伤结果的潜在生物标记物。 公共卫生相关性： 研究报告称，在最近战争中部署的退伍军人中，创伤后应激障碍的患病率很高(23%)。在我们对创伤后应激障碍的神经生物学、预防和有效的治疗干预的理解方面仍然存在重大差距。我们关于创伤后应激障碍的大部分知识来自于临床前模型和转化性研究。这篇优点评论的应用集中在神经肽Y(NPY)上，这是人类的一种压力弹性激素。在最近与辛辛那提退伍军人管理局的合作中，PI报告了患有创伤后应激障碍的退伍军人中NPY水平的降低(Sah等人，生物精神病学，2009)。目前的建议使用临床前创伤后应激障碍的啮齿动物模型来了解NPY与创伤后应激障碍的生理和治疗相关性。对患者护理的影响：本研究的目标是将NPY确定为潜在的干预目标和筛选创伤结局的预测性生物标记物。这些发现将为启动NPY筛查和补充的临床研究提供理论基础，以帮助退伍军人诊断创伤后应激障碍和改善治疗。