Investigation of the Central and Peripheral Inflammatory Mechanisms of PTSD Onset

PTSD发病的中枢和外周炎症机制研究

基本信息

批准号：
10707101
负责人：
Jessica Mary Gill
金额：
$ 81.44万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10707101
关键词：
Aberrant DNA Methylation Acute Address Adult Advanced Development American Amygdaloid structure Anterior Biological Biological Markers Bolus Infusion Calibration Caring Child Abuse Chronic Post Traumatic Stress Disorder Complex DNA Methylation Development Disease Endocrine Endocrine system Environmental Risk Factor Epigenetic Process Exhibits Family Genes Genetic Genetic Risk Glucocorticoids Grant Health Care Costs Heterogeneity Hippocampus Hormonal Hormones Hour Hydrocortisone Hypermethylation Immune Individual Inflammation Inflammatory Injury Investigation Knowledge Link Measures Mediating Medical Mental Health Methods Modification Molecular Neurobiology Neurons Participant Pathway interactions Peripheral Pharmacologic Substance Placebos Positron-Emission Tomography Post-Traumatic Stress Disorders Pre-Clinical Model Preventive Productivity Prospective Studies Proteins Protocols documentation Regulation Reporting Research Risk Risk Factors Sampling Shapes Societies Stress Structure Survivors Tracer Trauma Trauma patient Traumatic injury United States United States National Institutes of Health acute traumatic stress disorder biomarker discovery biomarker identification cingulate cortex combat cost cytokine experience fluorodeoxyglucose gene function health related quality of life high risk individual response mRNA Differential Displays neuronal metabolism novel physical conditioning post-traumatic stress prevent preventive intervention programs psychological symptom receptor recruit resilience response stressor suicidal individual technology development trauma centers trauma exposure traumatic event

项目摘要

DESCRIPTION (provided by applicant): Up to 90% of Americans experience a traumatic event, yet only 8 to 12% will then develop post-traumatic Stress disorder (PTSD), indicating that there is a high-level of inter-individual response to a trauma. The reasons for this heterogeneity are undoubtedly multi-factorial, and involve a complex interplay between genetic and environmental factors, that we are only starting to understand. Identification of biomarkers that are able to capture the genetic and environmental risks that contribute to PTSD risk would be of great benefit in directing preventive interventions; however, there are none currently available. We postulate that DNA methylation may be an ideal biomarker, as pre-existing PTSD risk factors result in altered DNA methylation of inflammatory regulating genes. High concentrations of inflammatory cytokines and insufficient endocrine regulation have been linked to PTSD onset. Therefore, it is plausible that epigenetic modifications serve to recalibrate an individual's biological response to a subsequent trauma, contributing to PTSD vulnerability. This relationship is not determined. These epigenetic modifications may also result in neuronal vulnerability, and contribute to PTSD onset. Previously we show that chronic PTSD is associated with inflammation which relates to alterations in glucocorticoid (GCR) sensitivity. Altered central GCR activity in the amygdala, hippocampus and anterior cingulate in preclinical models mediates neuronal vulnerability and PTSD onset. Central and peripheral GCR sensitivity changes may also contribute to inflammation and declines in health related quality of life (HRQOL). To address this critical issue the PI plans to develop a program of research to determine the biological predictors of PTSD onset, and the neurobiology that underlies PTSD onset. In this first study we will determine DNA methylation profiles in inflammatory regulating genes that predict PTSD onset, which may lead to the development of a biologically based method to identify individuals at highest risk for PTSD. In the second aim of this initial study, w will longitudinally examine the temporal development DNA methylation changes, and alterations in central and peripheral GCR sensitivity and HRQOL declines. We expect these findings to inform the development of effective preventative interventions.

描述（由申请人提供）：高达 90% 的美国人经历过创伤性事件，但只有 8% 至 12% 的人会出现创伤后应激障碍 (PTSD)，这表明个体间对创伤事件存在高度反应创伤。这种异质性的原因无疑是多因素的，涉及遗传和环境因素之间复杂的相互作用，而我们才刚刚开始了解这一点。识别能够捕获导致创伤后应激障碍风险的遗传和环境风险的生物标志物，对于指导预防性干预措施将大有裨益；然而，目前还没有可用的。我们假设 DNA 甲基化可能是一种理想的生物标志物，因为先前存在的 PTSD 危险因素会导致炎症调节基因的 DNA 甲基化发生改变。高浓度的炎症细胞因子和内分泌调节不足与 PTSD 的发病有关。因此，表观遗传修饰可能有助于重新调整个体对后续创伤的生物反应，从而导致 PTSD 脆弱性。这种关系尚未确定。这些表观遗传修饰也可能导致神经元脆弱性，并导致创伤后应激障碍（PTSD）的发生。之前我们发现慢性 PTSD 与炎症有关，而炎症又与糖皮质激素 (GCR) 敏感性的改变有关。在临床前模型中，杏仁核、海马体和前扣带回中枢 GCR 活性的改变介导神经元脆弱性和 PTSD 发作。中枢和外周 GCR 敏感性变化也可能导致炎症和健康相关生活质量 (HRQOL) 的下降。为了解决这一关键问题，PI 计划制定一项研究计划，以确定 PTSD 发病的生物学预测因子以及 PTSD 发病背后的神经生物学。在第一项研究中，我们将确定预测 PTSD 发作的炎症调节基因中的 DNA 甲基化谱，这可能会导致开发一种基于生物学的方法来识别 PTSD 风险最高的个体。在这项初步研究的第二个目标中，我们将纵向检查时间发育 DNA 甲基化的变化，以及中枢和外周 GCR 敏感性的变化以及 HRQOL 的下降。我们希望这些发现能够为制定有效的预防干预措施提供信息。