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: 10116484
• 负责人: ISABELLE M ROSSO
• 金额: $ 80万
• 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 2024-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10116484
• 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; Constitutional; Corticotropin; Corticotropin-Releasing Hormone; Coupling; DNA Methylation; DSM-V; Development; Diagnosis; Diagnostic; Diffusion Magnetic Resonance Imaging; Dimensions; Disease; Education; Elements; Epigenetic Process; Exposure to; Female; Fright; Functional Imaging; Functional Magnetic Resonance Imaging; Genes; Genetic; Genetic Predisposition to Disease; Genotype; Glutamate Metabolism Pathway; Glutamates; Glutamine; Heritability; Hormones; Hospitals; Human; Hydrocortisone; Individual; Knowledge; Link; Magnetic Resonance Spectroscopy; Major Depressive Disorder; 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; 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 实验室）：总结 创伤后应激障碍 (PTSD) 是全球疾病负担的主要原因，其发病率是全球疾病负担的两倍 女性和男性一样。除了女性之外，遗传因素也是 PTSD 的既定危险因素。 此外，诊断需要暴露于至少一种高度创伤性的压力源，该压力源独立地 与遗传脆弱性的协同作用会导致生物唤醒系统的长期扰动。一个 应激反应调节因素的数量可能会导致 PTSD，包括在 女性。促肾上腺皮质激素释放因子 (CRF) 和垂体腺苷酸环化酶激活功能改变 多肽（PACAP）系统代表了性别依赖性调节 PTSD 倾向的候选机制。 较高的血液 PACAP 水平和编码 PAC1R 受体的基因 (ADCYAP1R1) 的等位基因变异可预测 患有创伤后应激障碍 (PTSD) 的女性的焦虑唤醒症状和总体症状更严重，生理唤醒也更严重 在与焦虑相关的范例中。 CRF 及其 I 型受体的变异也与这两种疾病有关 创伤后应激障碍（PTSD）和抑郁症以及性别差异可能会导致暴露于以下环境的女性产生持续的生理唤醒： 严重的压力。重要的是，CRF/PACAP 的神经生物学相关性与唤醒相关的大脑重叠 与 PTSD 相关的电路，包括扩展杏仁核 (extAMG) 和内侧前额叶皮层 (mPFC)。 该项目旨在识别 CRF-、PACAP-、CRF+PACAP-主导的中间表型 患有创伤后应激障碍的女性和男性。 extAMG 的两个子区域：杏仁核 (AMG) 和纹状体床核 Terminalis (BNST)，将被独立检查，因为有证据表明它们在恐惧中部分分离的作用 与焦虑，以及它们对 PTSD 的潜在不同贡献。 mPFC 将成为一个区域的焦点 通过与 AMG 和 BNST 的相互连接来调节对威胁的唤醒反应。使用血液 来自患有 DSM-5 PTSD 的成年人的样本，我们将检查 CRF 和 PACAP 变异（遗传、表观遗传、mRNA） 与跨级别分析中的过度警觉标志物相关：(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)静息状态功能 extAMG-mPFC 的磁共振成像； (4)extAMG-mPFC的弥散张量成像； (5)磁性 mPFC 谷氨酸代谢和神经元完整性（N-乙酰天冬氨酸）的共振光谱； (6) 恐惧条件反射和黑暗增强惊吓范例期间的生理唤醒指标； (7) 临床 过度觉醒的症状：焦虑性觉醒、烦躁性觉醒和睡眠中断（使用自我报告和 体动记录仪）。项目 4 将增强我们对人类 CRF/PACAP 生物行为机制的理解， 具有识别新的 PTSD 生物标志物的潜力。 BNST 功能和谷氨酸代谢的神经影像学 特别具有创新性，可以促进针对个人改进诊断或治疗方法的开发 患有创伤后应激障碍。我们关注与其他 SPARED 项目相同的肽系统和大脑区域，并且我们 将利用整个中心的新发现来不断完善和优化我们的目标。