Sex-related variations in the response of drug therapies targeting purinergic signaling pathways in sepsis

靶向抗血小板药物治疗反应的性别相关差异 脓毒症嘌呤能信号通路 脓毒症是严重感染引起的一种复杂的临床综合征， 与高发病率和死亡率相关保健问题。当前脓毒症 治疗仅限于支持疗法和特定的药物治疗 可以大大改善病人的治疗效果， 据报道，受影响患者的死亡率高达50%，迫切需要 治疗脓毒症的改进方法。发病率和死亡率的性别差异 在各种临床研究和动物模型中已经观察到脓毒症。到目前为止， 在小鼠和人类中， 但缺乏对两性进行比较的研究 限制了我们评估性别差异程度的能力。但数据 迄今为止获得的数据表明，在确定 脓毒症的最佳药物干预。我们之前的研究表明， 在雄性小鼠中，靶向ADP受体P2 Y12的抗血小板治疗改善了 脓毒症的结果。然而，靶向另一种血小板ADP受体，P2 Y1没有 似乎能改变败血症此前的数据显示， 信令 的 的 P2y1 和 P2y12 激活和细胞内 在血小板中是复杂的和性别特异性的，然而， 数据尚不清楚。我们在免疫系统的其他细胞中缺乏类似的信息。 系统尚无研究调查靶向嘌呤能的性别相关差异 在败血症期间发出信号。因此，本项目旨在调查与性别有关的差异， 活化血小板的嘌呤能信号通路对药物治疗的反应 用于治疗败血症。我们将使用一个完善的败血症小鼠模型，如 雄性和雌性P2 Y12敲除（KO）和P2 Y1 KO中的盲肠结扎和穿孔 小鼠，并将其与野生型进行比较。我们将分析脓毒症的结果， 生存期、器官功能障碍、血浆细胞因子水平以及血小板 功能，如血小板-白细胞相互作用、血小板粘附标记物和血小板粘附标志物。 反应性本研究获得的数据将提供1）更全面的 了解脓毒症期间血小板行为的性别相关差异， 2）抗血小板药物在雄性和雌性小鼠中的有效性和安全性， 女性

Sex-related variations in the response of anti-platelet drug therapies targeting purinergic signaling pathways in sepsis Sepsis, a complex clinical syndrome resulting from a serious infection, is a major healthcare problem associated with high morbidity and mortality. Current sepsis treatments are limited to supportive therapies, and specific pharmacologic treatments that could greatly improve patient outcomes have not yet been developed With hospital mortality rates of affected patients reportedly as high as 50%, there is a critical need for improved methods for treating sepsis. Sex differences in the morbidity and mortality of sepsis have been observed in various clinical studies and animal models. To date, females has shown less mortality and decreased organ failure in mice and humans compared to their male counterpart but the lack of studies comparing both genders limits our capacity to evaluate the extent of sex-related differences. However, the data obtained so far suggest that sex should be taken into account when identifying the optimal pharmacological intervention for sepsis. Our previous studies have shown that in male mice, anti-platelet therapy that targets the ADP-receptor P2Y12 improves the outcome of sepsis. However, targeting another platelet ADP-receptor, P2Y1 did not seem to alter sepsis. Previous data have shown that the signaling of the P2Y1 and P2Y12 activation and intracellular are complex and sex-specific in platelets, however the data are still unclear. We are lacking similar information in other cells of the immune system. No studies have investigated sex-related differences in targeting purinergic signaling during sepsis. Hence this project aims to investigate sex-related differences in how the purinergic signaling pathways of activated platelets respond to drug therapies used for treating sepsis. We will use a well-established murine model of sepsis such as cecal ligation and puncture in male and female P2Y12 knock-out (KO) and P2Y1 KO mice and compared them with wild-type. We will analyze the outcome of sepsis in terms of survival, organ dysfunction, plasma cytokine levels, as well as platelet functions, such as platelet-leukocyte interaction, platelet adhesion markers and platelet reactivity. The data obtained in this study will provide 1) a more comprehensive understanding of sex-related differences in platelet behavior during sepsis between male and female mice, 2) the efficacy and safety of anti-platelet drugs in male and female.