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: 8398961
• 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/8398961
• 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; 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; screening; 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.

描述（由申请人提供）： 创伤后应激障碍（PTSD）是一种慢性且残疾的疾病，在经历创伤事件的个体中可能发生。鉴于PTSD的患病率上升，尤其是与战斗相关的患病率上升，因此对新型，有效的干预措施和与PTSD相关的临床前模型的研究目前很高。创伤后的恢复后不良和对PTSD的敏感性是韧性和应对压力受损的结果。 PTSD中还发现了人体应力调节系统的异常。神经肽Y（NPY）是一种主要发射器，与压力和焦虑的调节有关，并被认为是人类和啮齿动物中的“应力弹性因子”。在最近的研究中，我们报道了具有PTSD退伍军人的NPY脑脊液浓度较低。 NPY与PTSD的生理和治疗相关性具有很高的兴趣，但仍有待研究。该优点审查的应用建议在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和新颖，脑部Permeant NPY类似物的治疗潜力也将在创伤后筛选以获得恢复结果。慢性可变应力（CVS）的啮齿动物模型模拟了对战斗创伤的不可预测性，慢性和缺乏控制，并引用了PTSD样行为/生理学的表达。重要的是，我们的数据显示，杏仁核（PTSD个体失调的区域失调）持续存在CVS诱发的NPY缺陷。该应用的核心假设是杏仁核NPY的缺乏促进了焦虑，夸张的恐惧记忆（重新体验），惊吓（高音）和交感性的超速驱动的表达；并且补充NPY或外围注射的NPY类似物将促进对CVS诱导的缺陷的抵抗力/弹性。 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杏仁核NPY或NPY-Y2拮抗剂足以诱导耐晚期慢性应激引起的行为缺陷。总的来说，我们的数据将确定NPY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PTSD药物疗法的NPY类似物的发展提供理由，并作为预测创伤结果的潜在生物标志物。