微血管通透性增高是创伤后全身性炎症反应的标志性改变，可导致微循环稳态失衡。低温诱导型RNA结合蛋白（CIRP）是一个与创伤休克密切相关的新炎症介质，但CIRP能否直接引起内皮细胞屏障功能障碍，国内外均无报道。结合文献及前期研究，我们提出下列假设：CIRP通过与内皮细胞上的TLR4受体直接结合，激活Src-MLCK通路，导致细胞骨架收缩和细胞粘合分离，进而触发内皮通透性增高，是创伤失血性休克状态下导致微循环稳态失衡的重要原因。参与创伤休克器官损伤的炎症介质很多，为了排除其他已知及未知炎症介质的干扰，我们将首先确定CIRP对微血管内皮细胞的直接作用，然后确定CIRP对正常动物微血管通透性的作用，进而确定CIRP在失血性休克动物微血管通透性增高中的作用，并进一步确定微血管内皮细胞上CIRP作用的受体及CIRP导致微血管内皮细胞通透性增高的分子机制。本研究将为临床治疗微循环稳态失衡提供新的靶点。

Trauma is one of the world's leading causes of death and disability. Hemorrhagic shock is a major cause of morbidity and mortality following trauma. Around 40% of trauma-related deaths are due to hemorrhagic shock. Loss of large volume of blood in trauma patients results in deprivation of oxygen and nutrients in tissues, causing the systemic inflammatory response syndrome. As a hallmark of systemic inflammation, microvascular hyperpermeability occurs in multiple organ systems. Accumulated clinical and experimental evidence indicates that increases in microvascular permeability are involved in the development of multiple organ failure (MOF) following trauma and hemorrhagic shock. A better understanding of the mechanisms that regulate endothelial permeability is crucial to define the pathogenesis of trauma-associated tissue damage and to aid in the development of novel therapeutic approaches. Cold-inducible RNA-binding protein (CIRP) is a cold shock protein (CSP), which can be upregulated during cold stress, UV irradiation and hypoxia. Current understanding of the biological function of intracellular CIRP is to stabilize specific mRNAs and facilitate translation for survival advantage when cells are under stress conditions. However, our recent studies have produced an unexpected interesting discovery that disruption of the CIRP gene increases survival from hemorrhagic shock. Circulating levels of CIRP are increased in rats after hemorrhagic shock and in patients in the surgical ICU. We then examined the microvascular effects of extracellular CIRP and found that it directly caused endothelial barrier dysfunction. These data indicate an intriguing possibility that extracellular CIRP acts as a pathogenic factor in vascular inflammation. The objective of this project is to define the role and molecular mechanisms of extracellular CIRP-induced microvascular hyperpermeability under trauma-relevant inflammatory conditions. We will apply multidisciplinary in vitro and in vivo approaches to test the central hypothesis that CIRP triggers endothelial hyperpermeability signaling through direct engagement of TLR4 in endothelial cells and subsequent activation of the Src-MLCK pathway leading to cytoskeleton contraction and junction dissociation. We will 1) characterize the role of extracellular CIRP in regulating microvascular permeability; 2) identify the endothelial receptor involved in extracellular CIRP-medicated endothelial barrier disruption; and 3) define the molecular mechanisms by which extracellular CIRP increases endothelial permeability. Data derived from these studies will not only provide novel mechanistic insights into the pathophysiological regulation of microvascular barrier function during systemic inflammation, but also reveal a previously unappreciated therapeutic target for the treatment of trauma and hemorrhage.