PPARG rs10865710C/G影响创伤脓毒症发生风险的分子机制研究

Sepsis and Multiple Organ Dysfucntion Syndrome (MODS) are common and severe complications in trauma patients. There are still no effective early diagnosis methods. Peroxisome proliferator-activated receptor gamma (PPARγ) is a ligand-binding nuclear receptor, and its activation plays a prominent role in regulating the immune-inflammatory response. Our research found rs10865710C/G, located into the PPARG gene, which has close relationship with the incidence of sepsis and MODS after trauma through clinical association study In order to clarify the functional significance of the loci, this project will verify their relationship with the expression level and function of PPARG gene. Furthermore, the effect on transcriptional activity of PPARG gene, and transcription factors binding will be investigate respectively. A serial of in vitro experiments, such as report gene, EMSA, ChIP will be done to further prove our hypothesis. We will also constructed an early diagnose scoring model for severe trauma patients based on known risk factors, as well as the loci to verify and evaluate the usage of genetic factors in early diagnosis of traumatic sepsis using multiple-center cohorts. This study aimed to clarify the mechanism of the polymorphism affecting the prognosis of patients with severe trauma from functional level, and to investigate their diagnostic value for sepsis after trauma as well.

脓毒症及其引发的多器官功能障碍综合征是创伤后最常见的严重并发症，对人类健康造成巨大威胁，仍缺乏有效预测方法。过氧化物酶体增殖物激活受体γ（PPARγ）是一种依赖配体调节的转录因子，与免疫炎症应答反应密切相关。前期临床关联研究发现PPARG rs10865710C/G与创伤脓毒症和多器官功能障碍发生风险明显相关。为深入研究该位点在创伤脓毒症中的功能意义，本课题拟从其影响PPARG基因的转录活性、与转录因子结合能力、表达水平和功能活性等方面，利用报告基因、EMSA、ChIP等实验方法，系统阐述rs10865710C/G在创伤脓毒症中发挥作用的具体分子机制。并进一步在已知创伤脓毒症危险因素的基础上，复合该位点在全国多中心创伤人群建立并评价预警诊断模型的应用能力。研究旨在从功能水平上明确该位点影响创伤脓毒症发生风险的分子机制，并探讨其临床预警诊断价值。

脓毒症及其引发的多器官功能障碍综合征是严重创伤后最常见和致死的并发症，对人类健康造成巨大威胁，临床仍缺乏行之有效的早期预测方法。过氧化物酶体增殖物激活受体γ（PPARγ）是一种配体依赖性调节的核受体，与感染免疫炎症应答反应密切相关。本项目通过重庆和贵州地区两个临床中心遗传关联研究表明PPARG rs10865710C→G显著增加创伤脓毒症和多器官功能障碍发生风险，整合课题组前期发表的一个人群研究的meta分析证实了此位点的临床关联性；借助生物信息学、报告基因、EMSA和Western Blot等技术阐明了rs10865710C/G通过影响转录因子CREB2与PPARG基因增强子区域的结合能力，影响PPARG mRNA转录活性和蛋白表达水平，进一步在脓毒症发生风险性遗传关联研究系统评价和meta分析基础上，集成rs10865710C/G在重庆人群中初步建立了创伤脓毒症早期预警公式，为创伤脓毒症的早期识别提供思路。本项目从功能水平上明确了该位点影响创伤脓毒症发生风险的分子机制，并通过人群研究探讨了其临床早期预警价值。此外，本项目从lncRNA层面扩展了创伤脓毒症新的生物标志物探索和临床生化指标层面建立了创伤脓毒症预测模型，为创伤脓毒症的发生机制和早期综合预警奠定基础。