Transfer request of grant 1R21MH119561-01A1 (Deslauriers, Jessica) to Laval University

患有创伤后应激障碍(PTSD)的人心血管风险增加。然而， 心血管风险/高血压和创伤后应激障碍之间的因果关系尚不清楚， 创伤后应激障碍与心血管疾病高发病率的机制尚不清楚。 有证据表明，针对肾素的常用降压药的作用- 血管紧张素系统超越了降血压的范围，可能对创伤有治疗作用- 相关疾病，如创伤后应激障碍。血管紧张素II(Ang II)通过Ang-II型信号转导的机制 1受体(AT1R)影响创伤反应，症状尚不清楚。Ang-II在严重的疾病期间被释放 压力，而且有一些证据表明，中枢AT1aRs可能通过直接影响恐惧来影响创伤后应激障碍 电路激活。然而，另一种机制是，外周Ang II信号也可能有助于 中枢神经系统受炎性信号干扰导致的创伤后应激障碍的发生 在创伤期间和创伤后血脑屏障(BBB)的变化。BBB，通过成为分隔 外周和中枢系统，在中枢内稳态的调节中起着至关重要的作用。BBB完整性被以下因素破坏 高血压和严重应激，并与以下最强烈的创伤相关危险因素之一有关 创伤后应激障碍，创伤性脑损伤。AT1R激活GQ信号扰乱内皮细胞的紧密连接， 允许更大的分子，如蛋白质通过。在这里，我们认为严重的压力会增加 外周血管紧张素II，激活血管内皮细胞AT1R，导致血压升高和血脑屏障 渗透性。创伤引起的血脑屏障破坏可能会导致外周炎症的发生 向大脑发送信号分子，增加患创伤后应激障碍的风险。我们建议用细胞--来检验这一假设 类型特异性遗传和化学成因工具探索外周AT1aR信号对耐受的贡献 对创伤的中枢性炎症和行为反应。目标1将检验外周AT1aR的假设 信号对于创伤诱导的持续性中枢性炎症、创伤后应激障碍样行为的增加是必要的。目标 2将检验这一假设，即创伤期间和创伤后内皮细胞中的GQ/11信号足以干扰 改善血脑屏障的完整性，增加对创伤的持久炎症和行为反应。因此，拟议的 研究将确定外周和中枢肾素-血管紧张素系统之间的关系 增强中枢免疫信号和耐受创伤症状，并提供对其贡献的洞察 血脑屏障对创伤风险和症状维持的渗透性。

There is an increased cardiovascular risk in individuals with posttraumatic stress disorder (PTSD). However, the causal relationship between cardiovascular risk/hypertension and PTSD remains unclear, and the mechanisms underlying the high comorbidity of PTSD with cardiovascular diseases are not well understood. Evidence suggests that the actions of commonly used blood pressure medications that target the renin- angiotensin system extend beyond blood pressure reduction and may have therapeutic effects on trauma- related disorders, such as PTSD. The mechanisms for how angiotensin II (Ang II) signaling through Ang-II type 1 receptors (AT1R) affects trauma response and symptoms are not clear. Ang-II is released during severe stress, and there is some evidence for central AT1aRs to potentially affect PTSD through direct effects on fear circuit activation. An alternate mechanism however is that peripheral Ang II signaling may also contribute to development of PTSD through exposure of the central nervous system to inflammatory signaling via disruption of the blood brain barrier (BBB) during and after trauma. The BBB, by being the primary barrier separating the peripheral and central systems, is crucial in the regulation of central homeostasis. BBB integrity is disrupted by hypertension and severe stress, and is associated with one of the strongest trauma-related risk factors for PTSD, traumatic brain injury. AT1R activation of Gq signaling disrupts the tight junctions of endothelial cells, allowing larger molecules such as proteins to pass through. Here we propose that severe stress increases peripheral Ang II, which activates endothelial AT1Rs, leading to both increased blood pressure and BBB permeability. The trauma-induced BBB breakdown may then enable access of peripheral inflammatory signaling molecules to the brain, increasing the risk for PTSD. We propose to test this hypothesis by using cell- type specific genetic and chemogenic tools to probe the contribution of peripheral AT1aR signaling to enduring central inflammatory and behavioral responses to trauma. Aim 1 will test the hypothesis that peripheral AT1aR signaling is necessary for trauma-induced increases in enduring central inflammation PTSD-like behavior. Aim 2 will test the hypothesis that Gq/11 signaling in endothelial cells during and after trauma is sufficient to disrupt BBB integrity and increase enduring inflammatory and behavioral responses to trauma. Thus, the proposed studies will identify the relationship between peripheral and central renin-angiotensin system to lead to increased central immune signaling and enduring trauma symptoms, and provide insights into the contribution of BBB permeability to trauma risk and symptom maintenance.