Cell death proteins as inflammatory mediators in sepsis

败血症在美国是一个重要的公共卫生问题，每年导致30万人死亡，并产生 医疗保险受益人的费用超过600亿美元。因为我们并不完全了解感染是如何引发的 脓毒症所见的炎症调节失调，临床上尚无针对性的治疗方法。有耐心的 治疗仅限于针对感染的抗生素和针对器官衰竭的支持性护理。细胞死亡 信号通路，即控制细胞命运以响应环境刺激的机制，是分布的 在哺乳动物组织中广泛存在，是宿主防御入侵病原体的基本组成部分。 在感染期间，这些途径激活免疫反应，清除受感染的细胞，刺激组织破坏，以及 促进炎症。这一建议试图了解细胞死亡信号通路如何在 炎性失调是败血症的典型表现。这将通过分析以下这些通路的活性来完成 免疫组织和非免疫组织中的感染情况。从败血症患者身上采集的样本 将分析细胞死亡信号通路的活性，并将数据与临床变量相关联。 从这些观察中获得的见解将被用来指导旨在确定如何 这些通路在脓毒症期间受到调节。体外和体内技术都将在以下情况下使用 实验不能在人类病人身上进行。培养的人类细胞株将被感染并分析 在体外，细胞死亡信号通路抑制的效果将在脓毒症动物身上进行测量。结果来自 这项提议将更好地定义感染释放失控炎症的机制。 并提供对核心细胞稳态和防御机制如何发挥作用的更多了解 在危重疾病期间。这一知识将为致命的 疾病过程继续给现代医疗体系带来巨大压力。

Sepsis is a significant public health issue in the United States, killing 300,000 people each year and generating over $60 billion in costs to Medicare beneficiaries. Because we do not fully understand how infection triggers the inflammatory dysregulation seen in sepsis, no targeted therapies for sepsis are clinically available. Patient treatments are limited to antibiotics directed against infection and supportive care for organ failure. Cell death signaling pathways, the mechanisms that control cell fate in response to environmental stimuli, are distributed throughout mammalian tissue and are a foundational component of host defense against invading pathogens. During infection, these pathways activate immune responses, clear infected cells, incite tissue damage, and promote inflammation. This proposal seeks to understand how cell death signaling pathways contribute to the inflammatory dysregulation that typifies sepsis. This will be done by assaying activity of these pathways under conditions of infection in both immune and non-immune tissue. Samples collected from septic human patients will be analyzed for cell death signaling pathway activity and data will be correlated with clinical variables. Insights gained from these observations will be used to direct mechanistic studies aimed at determining how these pathways are regulated during sepsis. Both in vitro and in vivo techniques will be utilized when experiments cannot be performed in human patients. Cultured human cell lines will be infected and analyzed in vitro, and the effects of cell death signaling pathway inhibition will be measured in septic animals. Results from this proposal will better define the mechanisms through which infection unleashes dysregulated inflammation in sepsis and offer a greater understanding of how core cellular homeostasis and defense machinery functions during critical illness. This knowledge stands to produce novel therapeutic strategies and targets for a deadly disease process that continues to put tremendous strain on modern healthcare systems.