Cell death proteins as inflammatory mediators in sepsis

细胞死亡蛋白作为脓毒症炎症介质

• 批准号: 10715338
• 负责人: John Daniel Lyons
• 金额: $ 39.13万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10715338
• 关键词: Animals; Antibiotics; Apoptosis; Biological Assay; Cell Death; Cell Death Signaling Process; Cell Fate Control; Cells; Clinical; Critical Illness; Data; Disease; Healthcare Systems; Homeostasis; Host Defense; Human; Human Cell Line; Immune; Immune response; In Vitro; Infection; Inflammation; Inflammation Mediators; Inflammatory; Invaded; Knowledge; Measures; Medicare; Modernization; Organ failure; Pathway interactions; Patients; Persons; Process; Proteins; Public Health; Sampling; Sepsis; Signal Pathway; Stimulus; Supportive care; Techniques; Tissues; United States; beneficiary; cost; experimental study; in vivo; insight; novel therapeutic intervention; pathogen; programs; response; septic; targeted treatment; therapeutic target

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.

脓毒症是美国的一个重大公共卫生问题，每年造成30万人死亡，并产生 超过600亿美元的成本给医疗保险受益人。因为我们还不完全了解感染是如何 脓毒症中所见的炎症失调，临床上没有针对脓毒症的靶向治疗。患者 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，控制细胞命运的机制，对环境刺激的反应，分布在 在整个哺乳动物组织中，是宿主防御入侵病原体的基本组成部分。 在感染过程中，这些途径激活免疫反应，清除感染细胞，引发组织损伤， 促进炎症。该提案旨在了解细胞死亡信号通路如何有助于 典型的脓毒症的炎症失调。这将通过测定这些途径的活性来完成， 免疫和非免疫组织中的感染状况。从脓毒症人类患者中采集的样本 将分析细胞死亡信号通路活性，数据将与临床变量相关。 从这些观察中获得的见解将用于指导旨在确定 这些途径在脓毒症期间受到调节。在以下情况下，将使用体外和体内技术： 实验不能在人类患者身上进行。培养的人细胞系将被感染并在 体外，并且将在脓毒症动物中测量细胞死亡信号传导途径抑制的效果。结果 这一建议将更好地定义感染释放失调炎症的机制， 脓毒症，并提供更好的理解如何核心细胞稳态和防御机制的功能 在重病期间。这些知识将为致命的疾病产生新的治疗策略和目标。 疾病进程继续给现代医疗保健系统带来巨大压力。