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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

基本信息

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
项目类别：
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

项目摘要

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.

遭受人际暴力（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。具体的 IPV 的发育时机可能在疾病结果中发挥重要作用，其中经历过创伤青春期后期会使 PTSD 风险增加 3 倍。然而，人们对 IPV 和 PTSD 的时间效应知之甚少。与大脑发育和成熟的敏感期相关的风险。我们之前的研究考察了 IPV 在以黑人为主的成年人群体中，在特定的发育窗口期经历的健康结果女性。我们的结果显示，心理生理反应与 PTSD 风险、皮肤电导相关当 IPV 在 14 至 18 岁之间经历时，会独特地观察到反应 (SCR) 和恐惧增强的惊吓年在细胞外囊泡 (EV) 中使用无偏见的蛋白质组学方法来识别潜在的特异性生物标志物根据 IPV 经历的时间，我们发现了属于 17q21 基因簇的独特 EV 蛋白特征，并且与皮肤角质形成细胞有关，特别是默克尔细胞所独有的。默克尔细胞具有机械敏感性皮肤中的神经内分泌细胞受感觉 Ab 神经元支配，通过 Piezo2 检测光触刺激阳离子通道。我们在多模式感觉应激的小鼠模型中发现了类似的变化青春期经历的，包括与小鼠角蛋白 I 基因簇相关的 EV 蛋白 11qD，并增加成人恐惧增强的惊吓反应和冻结行为。综合起来，这些结果支持青春期后期基于触觉的创伤暴露可能会增加威胁电路的敏感性：拟议的跨物种转化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，我们有独特的机会来调查 30 年的自出生起就进行跟踪的前瞻性纵向黑人队列，包括在出生期间收集 IPV 数据青春期后期，并捕捉他们到成年早期的转变，提供对机制的深入了解以及与 PTSD 风险相关的生物标志物。我们要测试的首要假设是 IPV 发生在青春期后期的敏感期专门规划了沿着威胁-反应的不同生物途径轴涉及皮肤默克尔细胞-神经突复合体，并且这些变化是可检测到的生物标记物的测试目的如下： 1) 确定青春期后期是 IPV 的敏感期经验与急性威胁的心理生理措施有独特的联系，包括 SCR、恐惧- 对黑人男性和女性的前瞻性纵向出生队列进行强化惊吓和定量感官测试女性; 2) 从 EV 蛋白质组学检查中识别生物标志物以及与 PTSD 风险相关的特征来自前瞻性纵向队列； 3) 确定默克尔细胞参与电动汽车生产和使用小鼠青春期多模式感觉应激改变与 PTSD 风险相关的行为。