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，并导致难治性凝血障碍和 具有潜在可怕后果的炎症。矛盾的是，经常锻炼，这被认为是 提高我们对创伤的防御能力，增加显微镜下的内伤，从而增加 细胞损伤，如组蛋白，表明显微镜具有反直觉的保护或适应功能 内伤。这一概念有可能彻底改变我们对血管反应的看法 它可以帮助治疗创伤，并为新的治疗靶点提供洞察力。我们对血管是如何 排列在所有血管中的内皮细胞(ECs)感知创伤的光谱，并翻译创伤的信号 创伤转化为血管和免疫功能的改变，代表着一个重大的空白--但也是一个机会 我们的总体假设是组蛋白诱导的内皮细胞钙信号是 创伤到血管功能的翻译器。我们首先将重点放在两条钙离子内流途径上，即多模式 瞬时受体电位香草酸4(TRPV4)离子通道，以及离子亲性嘌呤能受体P2X7。在……里面 目的1，基于我们的新数据，我们探索了EC钙信号的性质，这表明生理学的 组蛋白水平激活TRPV4通道，创伤水平激活P2X7诱导钙内流。在目标2中， 我们探讨了组蛋白诱导的钙信号在血管反应中的功能后果，并进行了测试 保护创伤后血管内皮功能障碍的潜在策略。拟议的研究 预计该项目将显著推进改善临床结果所需的连续研究 精神创伤。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，提供一种 对我们更广泛地了解小血管在健康和疾病方面的持久和持久的影响。

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.