Impact of Trauma and its Products on Vascular Endothelial Function

严重的创伤会使我们的内源性止血系统不堪重负，并引起难治性凝血病， 炎症，可能会带来可怕的后果。奇怪的是，经常锻炼，这被认为是 提高我们对创伤的防御能力，增加微观内部损伤，从而增加 细胞损伤，如组蛋白，这表明显微镜的反直觉的保护或适应功能， 内伤这一概念有可能完全重塑我们对血管反应的看法， 创伤，并可以提供新的治疗靶点的见解。我们缺乏对血管 内皮细胞（EC）排列在所有血管中，感知创伤的频谱，并将创伤的信号转化为 创伤转化为血管和免疫功能的变化，代表了一个重要的空白，但也是一个机会 进行临床干预。 我们的总体假设是，组蛋白诱导的内皮细胞Ca2+信号是 将创伤转化为血管功能我们将首先关注两个Ca2+内流途径，多模态 瞬时受体电位香草酸4（TRPV4）离子通道和离子型嘌呤能受体P2X7。在 目的1，我们探索EC Ca 2+信号的本质，基于我们的新数据，这表明生理性 组蛋白水平参与TRPV4通道，创伤水平激活P2X7以诱导Ca2+进入。在目标2中， 我们探讨了组蛋白诱导的Ca2+信号对血管反应的功能性影响，并测试了 保护血管免受创伤后内皮功能障碍的潜在策略。拟议研究 该项目预计将显着推进研究的连续性，需要改善临床结果， 外伤此外，它有可能从根本上改变我们对内皮细胞生物学的看法， 对我们更广泛地理解健康和疾病中的小血管产生了持久和持续的影响。

Severe trauma can overwhelm our endogenous hemostatic systems, and cause refractory coagulopathy and inflammation with potentially dire consequences. Paradoxically, regular exercise, which is perceived as improving our defenses against trauma, increases microscopic internal injury and thereby byproducts of cellular damage, such as histones, suggesting a counterintuitive protective or adaptive function of microscopic internal injuries. This concept has the potential to completely remold our view of the vascular response to trauma and can provide insights into new therapeutic targets. Our lack of understanding of how vascular endothelial cells (ECs), which line all blood vessels, sense the spectrum of trauma, and translate the signals of trauma into changes in vascular and immune functions, represents a significant void—but also an opportunity for clinical intervention.  Our overall hypothesis is that histone-induced endothelial Ca2+ signaling is the translator of trauma to vascular functions. We will initially focus on two Ca2+ influx pathways, the polymodal transient receptor potential vanilloid 4 (TRPV4) ion channel, and the ionotropic purinergic receptor P2X7. In Aim 1, we explore the nature of EC Ca2+ signals, based on our novel data, which suggests that physiological levels of histones engage TRPV4 channels, and trauma levels activate P2X7 to induce Ca2+ entry. In Aim 2, we explore the functional consequences of histone-induced Ca2+ signaling on vascular responses, and test potential strategies to protect blood vessels from endothelial dysfunction after trauma. The proposed research project is expected to significantly advance the continuum of research needed to improve clinical outcomes in trauma. Moreover, it has the potential to radically change our view of endothelial cell biology, providing an enduring and sustained impact on our broader understanding of small vessels in health and disease.