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: 8043383
• 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/8043383
• 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; 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）是一种慢性和致残性疾病，可发生在经历创伤事件的个体中。鉴于PTSD的发病率不断上升，特别是与战斗有关的PTSD，寻找新的，有效的干预措施和临床前模型的研究是目前的高度优先事项。创伤后恢复不佳和易患创伤后应激障碍是恢复力和应对压力受损的结果。在PTSD中也发现了身体压力调节系统的异常。神经肽Y（NPY）是一种与压力和焦虑调节有关的主要递质，在人类和啮齿动物中被认为是一种“压力恢复因子”。在最近的研究中，我们报道了低浓度的神经肽Y在退伍军人创伤后应激障碍。神经肽Y与创伤后应激障碍的生理和治疗相关性是高度关注的，但仍有待研究。该Merit Review申请提出在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，还将筛选NPY和新型脑渗透性NPY类似物的治疗潜力以用于创伤后的恢复结果。慢性可变应激（CVS）的啮齿动物模型模拟战斗相关创伤的不可预测性、慢性性和缺乏控制，并引起PTSD样行为/生理学的表达。重要的是，我们的数据显示持续CVS诱发的杏仁核（PTSD患者中失调的区域）中NPY的缺陷。本申请的中心假设是，杏仁核NPY的缺乏促进焦虑、夸大的恐惧记忆（再体验）、惊吓（过度觉醒）和交感神经兴奋的表达;并且补充NPY或外周注射的NPY类似物将促进对CVS诱导的缺陷的抗性/恢复力。三个具体目标将调查这些假设：目的1验证暴露于CVS会导致杏仁核NPY系统延迟性和持续性失调的假设，目的2将检验CVS创伤前杏仁核NPY的缺陷将加剧CVS创伤诱发的行为和生理缺陷的假设。Y2拮抗剂足以诱导对晚期出现的慢性应激诱导的行为缺陷的抗性/恢复力。总的来说，我们的数据将确定神经肽Y在PTSD中的生理和潜在治疗相关性。相关性：这项临床前研究将为开发用于PTSD药物治疗的NPY类似物以及作为预测创伤结局的潜在生物标志物提供理论基础。 公共卫生关系： 研究报告称，在最近战争中部署的退伍军人中，PTSD的患病率很高（23%）。我们对PTSD神经生物学、预防和有效治疗干预的理解仍存在重大差距。我们对创伤后应激障碍的大部分知识都来自临床前模型和转化研究。这个优点审查应用程序的重点是神经肽Y（NPY），在人类的压力弹性激素。在最近与辛辛那提VA的合作中，PI报告了患有PTSD的退伍军人中NPY水平降低（Sah et al Biological Psychiatry 2009）。目前的建议使用临床前啮齿动物模型的创伤后应激障碍，以了解生理和治疗相关的神经肽Y创伤后应激障碍。对患者护理的影响：这项研究的目的是确定NPY作为一个潜在的干预目标和预测生物标志物，以筛选创伤的结果。研究结果将为启动NPY筛查和补充的临床研究提供理论依据，以帮助创伤后应激障碍的诊断和改善退伍军人的治疗。