Clinical studies of CRF-PACAP systems in human PTSD (Rosso)

CRF-PACAP 系统治疗人类 PTSD 的临床研究 (Rosso)

• 批准号: 10580001
• 负责人: ISABELLE M ROSSO
• 金额: $ 74.6万
• 依托单位: MCLEAN HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10580001
• 关键词: Adult; Affect; Alleles; Amygdaloid structure; Anxiety; Area; Arousal; Astrocytes; Biological; Biological Markers; Blood; Blood specimen; Brain; Brain region; Clinical; Clinical Research; Clinical assessments; Constitution; Constitutional; Corticotropin; Corticotropin-Releasing Hormone; Coupling; DNA Methylation; DSM-V; Darkness; Development; Diagnosis; Diagnostic; Diffusion Magnetic Resonance Imaging; Dimensions; Disease; Education; Elements; Epigenetic Process; Exposure to; Female; Fright; Functional Magnetic Resonance Imaging; Genes; Genetic; Genetic Predisposition to Disease; Genotype; Glutamate Metabolism Pathway; Glutamates; Glutamine; Heritability; Hormones; Hospitals; Human; Hydrocortisone; Image; Individual; Knowledge; Link; Magnetic Resonance Spectroscopy; Major Depressive Disorder; Maps; Measures; Medial; Mental Depression; Messenger RNA; Metabolism; N-acetylaspartate; Neurobiology; Neurons; Nightmare; PACAPR-1 protein; Patient Self-Report; Patients; Peptides; Peripheral; Phenotype; Physiological; Physiology; Post-Traumatic Stress Disorders; Prefrontal Cortex; Research; Research Domain Criteria; Rest; Risk; Risk Factors; Rodent; Role; Sex Differences; Sleep; Sleep Fragmentations; Sleep disturbances; Sleeplessness; Stress; Structure of terminal stria nuclei of preoptic region; Symptoms; System; Therapeutic; Time; Variant; Woman; Work; actigraphy; anxious; biobehavior; biological sex; brain circuitry; burden of illness; conditioned fear; design; follow-up; genetic risk factor; hypothalamic-pituitary-adrenal axis; improved; indexing; innovation; insight; men; neurobiological mechanism; neurochemistry; neuroimaging; pituitary adenylate cyclase activating polypeptide; program dissemination; receptor; response; sex; stressor; tractography; white matter

PROJECT 4 (ROSSO LAB): SUMMARY Post-Traumatic Stress Disorder (PTSD) is a leading cause of global disease burden, and it is twice as common in women as in men. In addition to female sex, genetic factors are established risk factors for PTSD. Furthermore, the diagnosis requires exposure to at least one highly traumatizing stressor, which independently and synergistically with genetic vulnerability leads to long-lasting perturbations in biological arousal systems. A number of moderators of stress responsiveness may contribute to PTSD, including the differential risk seen in women. Altered function of corticotropin releasing factor (CRF) and pituitary adenylate cyclase-activating polypeptide (PACAP) systems represent candidate mechanisms of sex-dependent moderation of PTSD liability. Higher blood PACAP levels and allelic variation in the gene (ADCYAP1R1) encoding the PAC1R receptor predict greater anxious arousal symptoms and total symptoms in women with PTSD, and greater physiological arousal during anxiety-related paradigms. Variation in CRF and its Type-I receptor have also been associated with both PTSD and depression, and sex differences may produce persistent physiological arousal in women exposed to severe stress. Importantly, the neurobiological correlates of CRF/PACAP overlap with arousal-related brain circuitry that is implicated in PTSD, including extended amygdala (extAMG) and medial prefrontal cortex (mPFC). This project is designed to identify CRF-, PACAP-, CRF+PACAP-predominant intermediate phenotypes in women and men with PTSD. Two subregions of the extAMG, the amygdala (AMG) and bed nucleus of the stria terminalis (BNST), will be independently examined, due to evidence of their partially separable roles in fear versus anxiety, and their potentially differential contributions to PTSD. The mPFC will be a focus as a region that modulates arousal responses to threat via reciprocal connections with the AMG and BNST. Using blood samples from adults with DSM-5 PTSD, we will examine CRF and PACAP variation (genetic, epigenetic, mRNA) in relation to markers of hyperarousal across levels of analysis: (1) blood levels of PACAP and hypothalamic pituitary adrenal axis hormones (ACTH and cortisol) as indices of CRF function; (2) resting state functional magnetic resonance imaging of extAMG-mPFC; (4) diffusion tensor imaging of extAMG-mPFC; (5) magnetic resonance spectroscopy of mPFC glutamate metabolism and neuronal integrity (N-acetylaspartate); (6) physiological indices of arousal during fear conditioning and dark enhanced startle paradigms; and (7) clinical symptoms of hyperarousal: anxious arousal, dysphoric arousal, and sleep disruption (using self-report and actigraphy). Project 4 will enhance our understanding of biobehavioral mechanisms of CRF/PACAP in humans, with the potential to identify new PTSD biomarkers. Neuroimaging of BNST function and glutamate metabolism is particularly innovative and may facilitate development of improved diagnostics or therapeutics for individuals with PTSD. We focus on the same peptide systems and brain regions as the other SPARED Projects, and we will use new discoveries from across the Center to continuously refine and optimize our objectives.

项目4（Rosso Lab）：摘要 创伤后应激障碍（PTSD）是全球疾病负担的主要原因，它是常见的两倍 在女性中，就像男人一样。除了女性外，遗传因素是PTSD的危险因素。 此外，该诊断需要至少暴露于一个高度创伤的压力源，这是独立的 与遗传脆弱性协同作用会导致生物唤醒系统的持久扰动。一个 压力反应能力的主持人数量可能会导致PTSD，包括 女性。皮质激素释放因子（CRF）和垂体腺苷酸环化酶激活的功能改变 多肽（PACAP）系统代表了PTSD责任的性别依赖性适度的候选机制。 编码PAC1R受体预测的基因（ADCYAP1R1）的较高的血PACAP水平和等位基因变异 PTSD女性的更大焦虑唤醒症状和总症状，生理唤醒越高 在与焦虑有关的范式中。 CRF及其I型受体的变化也与两者都相关 PTSD和抑郁症以及性别差异可能会导致妇女的持续生理唤醒 严重的压力。重要的是，CRF/PACAP与唤醒相关的大脑重叠的神经生物学相关性 与PTSD有关的电路，包括扩展的杏仁核（Extamg）和内侧前额叶皮层（MPFC）。 该项目旨在识别CRF-，PACAP-，CRF+PACAP-PREDOMINAL中级表型 有PTSD的男性和男性。 extamg的两个子区域，杏仁核（AMG）和Stria的床核 由于证据表明其在恐惧中部分可分离的作用，终端（BNST）将进行独立检查 与焦虑相对，及其对PTSD的潜在差异贡献。 MPFC将成为一个重点 这可以通过与AMG和BNST的相互连接来调节对威胁的唤醒响应。使用血液 来自DSM-5 PTSD的成年人的样品，我们将检查CRF和PACAP变异（遗传，表观遗传，mRNA） 关于跨分析水平的高伴星的标记：（1）PACAP和下丘脑的血液水平 垂体肾上腺轴激素（ACTH和皮质醇）作为CRF功能的指标； （2）静止状态功能 Extamg-MPFC的磁共振成像； （4）EXTAMG-MPFC的扩散张量成像； （5）磁性 MPFC谷氨酸代谢和神经元完整性（N-乙酰天冬酸酯）的共振光谱； （6） 恐惧调节和黑暗增强惊吓范式中唤醒的生理指标； （7）临床 高音症状：焦虑的唤醒，烦躁不安和睡眠中断（使用自我报告和 Actraphy）。项目4将增强我们对人类CRF/PACAP生物行为机制的理解， 有可能识别新的PTSD生物标志物。 BNST功能和谷氨酸代谢的神经影像学 特别是创新的，可以促进为个人改善诊断或治疗剂的开发 与PTSD。我们专注于与其他保留项目相同的肽系统和大脑区域，我们 将利用来自中心的新发现来连续完善并优化我们的目标。