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.

暴露于人际暴力（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，尤其是女性。具体 IPV的发育时间可能在疾病结局中起重要作用， 青春期后期PTSD风险增加3倍然而，很少有人知道IPV和PTSD的时间效应 与大脑发育和成熟的敏感期有关的风险。我们以前的研究检查了IPV 在以黑人为主的成年人队列中， 妇女我们的研究结果表明，心理生理反应与创伤后应激障碍的风险，皮肤电导， 反应（SCR）和恐惧增强惊吓，是唯一观察到的IPV经历了14-18 多岁在细胞外囊泡（EV）中使用无偏蛋白质组学方法来鉴定潜在的特异性生物标志物 IPV经历的时间，我们发现了属于17 q21基因簇的独特EV蛋白质签名， 与皮肤角质形成细胞相关，特别是默克尔细胞特有的。默克尔细胞是机械敏感的 皮肤中的神经内分泌细胞由感觉Ab神经元支配，通过Piezo 2检测轻触刺激 阳离子通道我们在一个小鼠模型中发现了类似的变化，在这个模型中， 包括与小鼠角蛋白I基因簇相关的EV蛋白 11 qD，并增加成人恐惧增强惊吓反应和冻结行为。综上所述各项 结果支持在青春期后期基于战斗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急性威胁结构。在这个提案中，我们有一个独特的机会来调查一个30年的 自出生以来一直接受随访的前瞻性纵向黑人队列，包括在 青春期后期，并捕捉他们的过渡，通过年轻的成年，提供深入了解的机制 和与PTSD风险相关的生物标志物。我们要检验的首要假设是，IPV发生在一个 青春期后期的敏感期特别地沿着威胁反应沿着不同的生物学途径 轴涉及皮肤默克尔细胞神经突复合体，这些变化是可检测的， 生物标志物的检测目的如下：1）确定青春期晚期是IPV的敏感期， 经验独特地与急性威胁的心理生理学测量相关联，包括SCR，恐惧， 在黑人男性的前瞻性纵向出生队列中进行增强惊吓和定量感觉测试， 2）从EV蛋白质组学检查中鉴定生物标志物和与PTSD风险相关的特征 3）鉴定参与EV产生的默克尔细胞， 在小鼠中使用青春期多模态感觉应激改变与PTSD风险相关的行为。