血管内皮SDC-1诱发创伤性凝血病的分子机制研究

Acute traumatic coagulopathy (ATC) is a severe complication of trauma. The lack of reliable and effective targets for early diagnosis makes it tend to be misdiagnosed. Mortality rates of trauma patients with ATC may rise up to 50%. New research suggests that traumatic hemorrhagic shock often induces disruption and shedding of the vascular endothelium glycocalyx, which may be an important triggering factor of ATC. Our team had found that the plasma level of SDC-1, a marker of endothelial glycocalyx degradation, was positively correlated with the severity of trauma patients. In addition, the increase in the concentration of SDC-1 appeared in early post-trauma. Then we hypothesized that vascular endothelial SDC-1 could play a vital role in triggering and inducing ATC. However, what are triggering mechanism and key links among SDC-1 in the occurrence and development of ATC? The answer is still unknown so far. On the basis of our previous work, pcDNA3.0-unshedding-SDC-1 and low expression vector of SDC-1will be constructed. The present study is intended to clarify the possible molecular mechanism of SDC-1 in the inducing of ATC, and determine the role of SDC-1 in the occurrence of ATC. The expected results could expand the understanding of the relationship between SDC-1and pathological mechanism of ATC, and provide clinical theoretical reason for finding a new alert target involved during ATC.

急性创伤性凝血病（ATC）是常见的创伤合并症，因缺乏可靠有效的早期诊断指标，容易漏诊误诊，其死亡率可高达50%。最新研究提示，创伤失血性休克时血管内皮糖萼层常遭破坏受损，其可能是ATC的重要触发因素。前期课题组研究发现创伤患者血管内皮糖萼脱落标志物（SDC-1）的水平与创伤严重程度呈正相关，且创伤后较早升高于血浆中。我们推测，血浆SDC-1在启动和诱发ATC中发挥着至关重要的作用。然而SDC-1诱发ATC的启动机制和关键环节是什么？国内外相关文献尚未阐明。本课题拟在前期工作基础上，通过构建大鼠SDC-1不脱落真核表达载体和低表达等基因修饰动物模型，阐明SDC-1诱发ATC的分子机制，明确血管内皮糖萼在ATC发生中的重要作用；拓展对SDC-1和ATC病理机制之间关系的认识，为发现ATC早期预警新靶点提供临床理论依据。

研究背景：SDC-1在多项临床研究中被认为是创伤休克患者预后不良因素，但缺乏具体的机制研究。研究内容：为了阐释SDC-1在休克中的具体机制，课题组首先观察了临床患者和动物模型中SDC-1表达情况，通过干预和过表达SDC-1的发生，观察SDC-1对休克的具体作用。利用细胞生物学实验手段探究具体的作用机制。重要结果及关键数据：研究结果显示，临床创伤休克患者外周血SDC-1表达确实明显升高。但是补充SDC-1减轻了动物模型组织损伤和凝血异常，通过SDC-1基因敲除小鼠发现SDC-1敲除增加了死亡率，加重了炎症损伤。这个结果推翻了学界认为脱落的SDC-1促进了创伤休克不良预后的论断。通过细胞生物学实验发现，创伤休克后HIF-1α促进了SDC-1的表达，脱落的SDC-1阻断了NLRP3诱导的细胞焦亡，减少了炎症因子的分泌。利用IP技术发现SDC-1可能通过血管性血友病因子（vWF）分子影响了凝血功能，通过HMGB1分子影响了细胞焦亡通路。至此，课题初步改变了对SDC-1原有的认识，初步探讨了SDC-1在创伤休克中的作用效果和可能作用机制。科学意义：课题通过严谨的实验构思、可靠的实验手段、详实的数据结果，得出SDC-1可能是改善创伤休克不良预后的关键因素，通过一系列分子调控实验，基因测序，基因敲除动物，小分子化合物，荧光标记蛋白，细胞间互作模型，免疫共沉淀，荧光素酶报告载体的当前较为先进的实验手段，揭示了SDC-1改善创伤休克不良预后的可能作用机制，为临床快速靶向治疗，减少创伤休克不良预后寻找到了一个新的靶点。

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