Extracellular vesicles as biomarkers of trauma exposure and PTSD risk

细胞外囊泡作为创伤暴露和 PTSD 风险的生物标志物

• 批准号: 10420911
• 负责人: Tracy L Bale
• 金额: $ 76.9万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10420911
• 关键词: 17q21; Acute; Adolescence; Adolescent; Adult; Age; Behavior; Biological; Biological Markers; Birth; Black race; Brain; Cations; Characteristics; Childhood; Chronic; Collection; Complex; Data; Development; Discrimination; Disease Outcome; Exposure to; Freezing; Fright; Galvanic Skin Response; Gene Cluster; Health; Human; Individual; Interpersonal Violence; Intervention; Keratin; Light; Link; Longevity; Longitudinal cohort; Measures; Mental Health; Merkel Cells; Molecular; Mus; Neurites; Neuroendocrine Cell; Neurons; Outcome; Pathway interactions; Physiological; Piezo 2 ion channel; Play; Population; Post-Traumatic Stress Disorders; Production; Proteins; Proteomics; Psychophysiology; Reporting; Research Domain Criteria; Resources; RiboTag; Risk; Role; Sensory; Sensory Thresholds; Skin; Startle Reaction; Stimulus; Stress; Tactile; Testing; Tissues; Touch sensation; Trauma; Woman; age group; base; black men; black women; cohort; conditioned fear; designer receptors exclusively activated by designer drugs; disorder risk; emotional abuse; experience; extracellular vesicles; insight; keratinocyte; men; mouse model; multimodality; nanoparticle; neurophysiology; novel; novel marker; potential biomarker; programs; prospective; response; specific biomarkers; tactile stimulation; transcriptomics; translational study; trauma exposure; violence exposure; young adult; zeta potential

Exposure to interpersonal violence (IPV) is associated with long-term negative mental health consequences, including an increased risk for posttraumatic stress disorder (PTSD), especially in women. The specific developmental timing of IPV is likely to play a significant role in disease outcomes where trauma experienced in late adolescence increases PTSD risk by 3-fold. However, little is known as to timing effects of IPV and PTSD risk related to sensitive periods of brain development and maturation. Our previous studies examined IPV experienced during specific developmental windows on health outcomes in a predominantly Black cohort of adult women. Our results revealed that psychophysiological reactivity related to PTSD risk, skin conductance response (SCR) and fear-potentiated startle, was uniquely observed when IPV was experienced between 14-18 yrs. Using an unbiased proteomic approach in extracellular vesicles (EV) to identify potential biomarkers specific to timing of IPV experience, we found a unique EV protein signature belonging to a 17q21 gene cluster and associated with skin keratinocytes, specifically unique to Merkel cells. Merkel cells are mechanosensitive neuroendocrine cells in the skin innervated by sensory Ab neurons that detect light touch stimuli via Piezo2 cation channels. We found similar changes in a mouse model in which multimodal sensory stress was experienced during the pubertal period, including EV proteins associated with the mouse keratin I gene cluster 11qD, and increased adult fear-potentiated startle responses and freezing behaviors. Taken together, these results support tactile-based trauma exposure during late adolescence may increase sensitivity of threat circuitry: the proposed cross-species translational study will examine molecular and physiological levels of analyses of the RDoC Acute Threat construct. In this proposal, we have the unique opportunity to investigate a 30-yr prospective longitudinal Black cohort who have been followed since birth, including collection of IPV data during late adolescence, and to capture their transition through young adulthood, providing insight into the mechanisms and biomarkers related to PTSD risk. Our overarching hypothesis to be tested is that IPV occurring during a sensitive period of late adolescence specifically programs distinct biological pathways along the threat-response axis involving the skin Merkel cell-neurite complex, and that these changes are detectable as accessible biomarkers to be tested in the following Aims: 1) To establish that a sensitive period of late adolescence for IPV experience uniquely associates with psychophysiological measures of acute threat, including SCR, fear- potentiated startle, and quantitative sensory testing in a prospective longitudinal birth cohort of Black men and women; 2) To identify biomarkers from examination of EV proteomics and characteristics relevant to PTSD risk from a prospective longitudinal cohort; and 3) To identify the Merkel cell involvement in production of EVs and alteration of behaviors relevant to PTSD risk using pubertal multimodal sensory stress in a mouse.

接触人际暴力(IPV)与长期的负面心理健康后果有关， 包括增加患创伤后应激障碍(PTSD)的风险，尤其是在女性中。具体的 IPV的发育时机可能在创伤所经历的疾病结局中发挥重要作用 青春期晚期，创伤后应激障碍的风险增加3倍。然而，对IPV和PTSD的时间效应知之甚少 与大脑发育和成熟的敏感期有关的风险。我们之前的研究检查了IPV 在以黑人为主的成人队列中的特定发育窗口中经历的健康结果 女人。我们的结果显示，心理生理反应与创伤后应激障碍的风险、皮肤传导性有关。 反应(SCR)和恐惧增强的惊吓，在14-18岁之间经历IPV时被独特地观察到 几年前。在细胞外小泡(EV)中使用无偏倚的蛋白质组学方法来识别潜在的特定生物标志物 对于IPV体验的时间，我们发现了一个独特的EV蛋白特征，属于17q21基因簇和 与皮肤角质形成细胞有关，尤其是默克尔细胞所特有的。默克尔细胞对机械敏感 皮肤中的神经内分泌细胞由通过Piezo2探测光触摸刺激的感觉抗体神经元支配 阳离子通道。我们在小鼠模型中发现了类似的变化，在该模型中，多模式感觉应激 在青春期经历，包括与小鼠角蛋白I基因簇相关的EV蛋白 11qd，成虫恐惧增强的惊吓反应和冰冻行为。这些加在一起， 结果青春期晚期基于支持触觉的创伤暴露可能会增加威胁回路的敏感性： 拟议的跨物种翻译研究将检查分子和生理水平的分析 RDoC急性威胁构建。在此计划中，我们有独一无二的机会来调查30年来 从出生起就被跟踪的预期纵向黑人队列，包括在 青春期晚期，并捕捉他们通过青春期的转变，提供对机制的洞察 以及与创伤后应激障碍风险相关的生物标志物。我们要检验的主要假设是，IPV发生在 青春期后期的敏感期在威胁-反应过程中特别规划了不同的生物途径 涉及皮肤Merkel细胞-轴突复合体的轴，这些变化是可以检测到的 生物标志物将在以下方面进行测试：1)确定IPV的青春期晚期敏感期 体验与严重威胁的心理生理指标具有独特的联系，包括SCR、恐惧- 在黑人男性和男性的前瞻性纵向出生队列中加强惊吓和定量感觉测试 女性；2)通过EV蛋白质组学检查和与创伤后应激障碍风险相关的特征确定生物标记物 3)确定默克尔细胞参与生产电动汽车和 利用青春期多模式感觉应激在小鼠中改变与创伤后应激障碍风险相关的行为。