Psychological deficits after low level blast exposure: role of neurovascular disruption

低水平爆炸暴露后的心理缺陷：神经血管破坏的作用

• 批准号: 9890125
• 负责人: William Brad Hubbard
• 金额: --
• 依托单位: VA MEDICAL CENTER - LEXINGTON, KY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9890125
• 关键词: 3-Dimensional; Acute; Address; Affect; Aggressive behavior; Aging; Amygdaloid structure; Animal Model; Animals; Anxiety; Behavior; Behavior assessment; Behavioral; Bioenergetics; Biological Assay; Biological Markers; Blast Injuries; Blood - brain barrier anatomy; Blood Platelets; Blood Vessels; Brain; Brain region; Cerebrovascular Circulation; Chronic; Chronic Post Traumatic Stress Disorder; Clinical; Coupled; Data; Development; Development Plans; Exposure to; Foundations; Functional disorder; Grant; Health; Image; Immunohistochemistry; Impairment; Investigation; Kentucky; Knowledge; Lead; Life; Literature; Matrix Metalloproteinases; Measures; Mentors; MicroRNAs; Military Personnel; Modeling; Nervous System Trauma; Neurocognitive; Neurologic Deficit; Neurologic Dysfunctions; Neurological outcome; Neurons; Neuropsychology; Occupational; Occupational Exposure; Outcome; Pathologic; Peripheral; Phenotype; Population; Post-Traumatic Stress Disorders; Predisposition; Proteins; Publishing; Rattus; Recording of previous events; Recovery; Reporting; Research; Research Personnel; Risk; Rodent; Rodent Model; Role; Serum; Social Interaction; Soldier; Spin Labels; Stains; Symptoms; Techniques; Testing; Therapeutic; Time; Tissues; Training; Training Programs; Universities; Vascular Diseases; Veterans; Writing; base; behavior test; behavioral impairment; blood-based biomarker; blood-brain barrier disruption; career development; cerebrovascular; clinically relevant; cohort; depressive symptoms; exosome; experience; improved; inhibitor/antagonist; multimodality; neuroimaging; neuropathology; neurovascular; neurovascular unit; novel; operation; phosphodiesterase V; pre-clinical; primary outcome; programs; psychologic; psychological outcomes; restoration; sildenafil; skills; stress related disorder; student mentoring; therapeutic target; time interval; trait

Many Veterans experience occupational exposure to low-level blast (LLB) during normal training operations, including but not limited to breaching activity. These Veterans are at increased risk for persisting neuropsychological impairment due to repeated LLB exposure over several deployments with limited time for recovery between exposures. The extent of the long-term consequences after cumulative LLB exposure is unknown, though reports show that deficits can be present late in life. Furthermore, the resultant post-traumatic stress disorder (PTSD)-related behavioral deficits are more pronounced in soldiers and Veterans with a history of chronic blast exposure. There is no clear understanding of which pathological mechanisms drive this chronic PTSD phenotype after LLB exposure. A few animal models have been established to address this incomplete understanding of the pathobiological mechanisms underlying LLB exposure. These models replicate the chronic depressive, anxiogenic, and PTSD-related traits observed in Veterans, though there are many knowledge gaps in what contributes to these chronic deficits. In general, blast exposure causes acute blood- brain barrier (BBB) and neurovascular unit abnormalities that can persist over time. The overall objective of this application is to determine the timing of acute neurovascular dysfunction after LLB and how repeating LLB contributes to chronic neurovascular impairment and neuropsychological deficits. Our central hypothesis is that LLB repeated at a time interval of maximal BBB impairment, after the first LLB, will result in persistent PTSD- like behavioral traits. Additionally, these deficits will be associated with changes in the profile of serum-derived exosomal miRNAs and platelet bioenergetics. These hypotheses were formulated based on current literature and our own published and preliminary data demonstrating anxiety and amygdalar BBB disruption after blast exposure. By utilizing a multimodal blast simulator at the University of Kentucky, these studies will be able to examine the longitudinal behavioral profile, coupled with pathologically relevant biomarkers. These hypotheses will be tested in three specific aims: 1) examine acute neurovascular deficits after a single LLB exposure and determine their relationship to longitudinal behavioral traits, 2) determine how repeating LLB at various time intervals, based on the acute neurovascular profile, contributes to exacerbated or prolonged PTSD-like behavioral traits and chronic neurovascular impairment, 3) identify if modulating either acute or chronic neurovascular health using sildenafil will mitigate long-term PTSD-like behavioral traits. This research will drastically improve our understanding of the effects of LLB as well as potentially identify novel, clinically- relevant biomarkers. The proposed research is significant because it will establish a platform to understand the chronic effects of occupational blast exposure, which affects many Veterans. In addition, this line of investigation can lead to better therapeutic targeting of neurovascular dysfunction to improve neurological outcome in aging Veterans. In addition to the research products gained by this proposal, the applicant will greatly benefit from a mentoring team that has a variety of preclinical, translational, and clinical perspectives, which will contribute to a well-rounded career development plan. The training program will add additional techniques to Dr. Hubbard’s’ repertoire, contributing not only to this proposal but to his VA research program moving forward. With prior knowledge in blast injury modeling, additional behavioral and biomarker assays will greatly advance his research expertise. In the latter years of this proposal, Dr. Hubbard will continue to expand grant writing, student mentoring, collaborative research and presentation skills required of independent researchers. Overall, the proposed studies and diverse mentoring program will culminate in producing a highly successful independent VA researcher.

许多退伍军人在正常训练期间都经历过低强度爆炸（LLB）的职业暴露， 包括但不限于违规活动，这些退伍军人持续面临更大的风险。 由于在多次部署中反复暴露于有限的时间而导致的神经心理损伤 累积 LLB 暴露后的长期后果的程度是 尽管报告显示缺陷可能会在晚年出现，但尚不清楚。此外，由此产生的创伤后症状。 与应激障碍 (PTSD) 相关的行为缺陷在有病史的士兵和退伍军人中更为明显 慢性爆炸暴露的病理机制尚不清楚。 已经建立了一些动物模型来解决 LLB 暴露后的 PTSD 表型。 了解 LLB 暴露背后的病理生物学机制。 在退伍军人中观察到慢性抑郁、焦虑和创伤后应激障碍（PTSD）相关特征，尽管有很多 一般来说，爆炸暴露会导致急性血液损伤。 脑屏障（BBB）和神经血管单元异常可能会随着时间的推移而持续存在。 应用是确定LLB后急性神经血管功能障碍的时间以及如何重复LLB 导致慢性神经血管损伤和神经心理缺陷。我们的中心假设是： 在第一次 LLB 之后，以最大 BBB 损伤的时间间隔重复 LLB，将导致持续的 PTSD- 此外，与行为特征一样，这些缺陷也与血清来源的特征的变化有关。 这些假设是根据现有文献制定的。 我们自己发表的初步数据显示爆炸后焦虑和杏仁核 BBB 破坏 通过利用肯塔基大学的多模式爆炸模拟器，这些研究将能够 检查纵向行为特征以及病理相关的生物标志物。 将针对三个具体目标进行测试：1）检查单次 LLB 暴露后的急性神经血管缺陷，以及 确定它们与纵向行为特征的关系，2）确定如何在不同时间重复法学学士学位 基于急性神经血管特征的间隔会导致类似 PTSD 的加剧或延长 行为特征和慢性神经血管损伤，3) 确定调节是急性还是慢性 使用西地那非的神经血管健康将减轻长期的 PTSD 样行为特征。 极大地提高了我们对法学学士的影响的理解，并有可能识别出新的、临床上的 拟议的研究意义重大，因为它将建立一个了解相关生物标志物的平台。 职业爆炸暴露的慢性影响，影响着许多退伍军人。 研究可以更好地针对神经血管功能障碍进行治疗，从而改善神经功能 除了通过该提案获得的研究成果外，申请人还将获得老年退伍军人的成果。 受益于具有各种临床前、转化和临床视角的指导团队， 这将有助于制定全面的职业发展计划。培训计划将增加额外的内容。 Hubbard 博士的全部技术，不仅为这项提案做出了贡献，而且为他的 VA 研究计划做出了贡献 展望未来，凭借爆炸损伤模型的先验知识，将进行额外的行为和生物标志物测定。 在这项提案的后几年，哈伯德博士将继续扩展他的研究专业知识。 独立所需的资助写作、学生指导、协作研究和演讲技巧 总体而言，拟议的研究和多样化的指导计划将最终产生高度的成果。 成功的独立 VA 研究员。