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

许多退伍军人在正常的训练操作中经历了职业暴露于低水平冲击波(LLB)， 包括但不限于违规活动。这些退伍军人坚持下去的风险更大 在有限的时间内，在几次部署中重复暴露LLB造成的神经心理损害 两次曝光之间的恢复。累积LLB风险敞口后的长期后果程度如下 未知，尽管报告显示，缺陷可能会出现在生命的后期。此外，由此产生的创伤后 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 慢性冲击波暴露。目前还不清楚是什么病理机制导致了这种慢性疾病。 暴露后的创伤后应激障碍表型。已经建立了一些动物模型来解决这种不完全的问题 了解潜在的LLB暴露的病理生物学机制。这些模型复制了 在退伍军人中观察到慢性抑郁、焦虑症和创伤后应激障碍相关的特征，尽管有许多 在造成这些长期赤字的原因方面存在知识差距。一般来说，冲击波暴露会导致急性血液- 脑屏障(BBB)和神经血管单位的异常，可持续一段时间。这样做的总体目标是 应用是确定LLB后急性神经血管功能障碍的时间以及LLB如何重复 会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，以最大血脑屏障损害的时间间隔重复LLB，将导致持续性PTSD- 比如行为特征。此外，这些缺陷将与血清来源的图谱的变化有关 外体miRNAs和血小板生物能量学。这些假设是基于当前文献提出的。 我们自己公布的初步数据显示爆炸后焦虑和杏仁核血脑屏障中断 曝光。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，结合病理相关的生物标记物。这些假设 将在三个具体目标中进行测试：1)检查单一LLB暴露后的急性神经血管缺陷和 确定它们与纵向行为特征的关系，2)确定在不同时间重复LLB的方式 基于急性神经血管特征的间期，会导致类似创伤后应激障碍的加重或延长 行为特征和慢性神经血管损害，3)确定是急性还是慢性调节 使用西地那非的神经血管健康将缓解长期的创伤后应激障碍样行为特征。这项研究将 极大地提高了我们对LLP影响的理解，并有可能在临床上发现新的- 相关生物标志物。这项拟议的研究具有重要意义，因为它将建立一个了解 职业性爆炸暴露的慢性影响，这影响到许多退伍军人。此外，这条线路 研究可以更好地针对神经血管功能障碍进行治疗，以改善神经功能 退伍军人老龄化的结局。除了通过这项建议获得的研究产品外，申请人还将 极大地受益于拥有各种临床前、翻译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 哈伯德博士的全套技术，不仅为这一提议做出了贡献，也为他的VA研究计划做出了贡献 继续前进。有了爆炸伤模型的先验知识，额外的行为和生物标记物分析将 大大提高了他的研究水平。在这项提议的最后几年，哈伯德博士将继续扩大 独立工作所需的写作、学生指导、协作研究和演讲技巧 研究人员。总体而言，拟议的研究和多样化的指导计划将最终产生一个高度 成功的独立退伍军人事务部研究员。

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.