PKR mediated inflammasome activation and pyroptosis in sepsis

脓毒症中 PKR 介导的炎症小体激活和细胞焦亡

• 批准号: 8496322
• 负责人: Kevin J Tracey
• 金额: $ 32.02万
• 依托单位: FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-15 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8496322
• 关键词: Animals; Apoptosis; Autopsy; Caspase; Cause of Death; Cell Death; Cells; Clinic; Clinical; Complex; Data; Functional disorder; Gel Chromatography; Genetic; HMGB1 gene; Health; Hospital Mortality; Immunoprecipitation; Incidence; Infection; Inflammatory; Injury; Interleukin-1; Interleukin-18; Knowledge; Lilly brand of drotrecogin alfa activated; Mediating; Modality; Mus; Nature; Organ; Pathogenesis; Pathology; Pathway interactions; Patients; Phosphotransferases; Prevention; Public Health; Reporting; Role; Secondary to; Sepsis; Septic Shock; Signaling Protein; Syndrome; Techniques; Therapeutic; Therapeutic Agents; United States; Work; abstracting; genetic regulatory protein; innovation; mortality; novel strategies; prevent; public health relevance; reconstitution; therapeutic target; tool

DESCRIPTION (provided by applicant): Project summary/abstract Severe sepsis is a clinical syndrome occurring in patients with severe injury or infection, with an annual incidence of approximately 750,000 cases in the United States. The mortality rate is 20-30%, and currently there are no specific therapeutic agents approved for clinical use. Indeed, the only specifically approved agent (Xigris) was recently withdrawn from the clinic because of poor efficacy. Autopsy studies have shown that the major cell death mechanism in severe sepsis victims is via programmed cell death through two major pathways, termed "apoptosis" and "pyroptosis." Prior efforts to prevent cell death by blocking the inflammasome had been extremely difficult, because until recently, the identity of a major regulatory protein that controls the inflammasome was unknown. However, an innovative discovery has now revealed the identity of the key regulatory protein that is required for activation of the inflammasome: it is a kinase termed "PKR." We have reported this discovery in Nature, and it now enables us to directly target the inflammasome by inhibiting PKR; this also prevents programmed cell death. The objective of this proposal is to study the role of these PKR pathways in the pathogenesis of sepsis. We will use an innovative new approach to focus on the overall hypothesis that pyroptosis during severe sepsis is deleterious, and that inhibiting pyroptosis by inactivating PKR-dependent inflammasome activation will be beneficial to the host. This will be accomplished in three Aims: Specific Aim 1. Role of PKR as an essential regulator of pyroptosis; Specific Aim 2. Role of PKR in inflammasome assembly; and Specific Aim 3. PKR as a therapeutic target in sepsis. The results of this innovative approach should reveal the mechanisms of cell death in severe sepsis, and open a pathway to preventing it with agents that inhibit PKR.

描述（由申请人提供）： 项目摘要/摘要 严重脓毒症是一种发生在严重损伤或感染患者中的临床综合征，在美国每年发病率约为 750,000 例。死亡率为20-30%，目前尚无批准用于临床的特异性治疗药物。事实上，唯一专门批准的药物（Xigris）最近因疗效不佳而从临床撤出。尸检研究表明，严重脓毒症患者的主要细胞死亡机制是通过两个主要途径（称为“细胞凋亡”和“细胞焦亡”）进行程序性细胞死亡。之前通过阻断炎症小体来防止细胞死亡的努力极其困难，因为直到最近，控制炎症小体的主要调节蛋白的身份仍然未知。然而，一项创新发现现已揭示了炎症小体激活所需的关键调节蛋白的身份：它是一种称为“PKR”的激酶。我们已经在 Nature 上报道了这一发现，现在它使我们能够通过抑制 PKR 来直接靶向炎症小体；这也可以防止程序性细胞死亡。本提案的目的是研究这些 PKR 通路在脓毒症发病机制中的作用。我们将使用一种创新的新方法来关注这样一个总体假设：严重脓毒症期间的细胞焦亡是有害的，而通过灭活 PKR 依赖性炎症小体激活来抑制细胞焦亡将对宿主有益。这将通过三个目标来实现： 具体目标 1. PKR 作为细胞焦亡的重要调节剂的作用；具体目标2. PKR在炎性小体组装中的作用；具体目标 3. PKR 作为脓毒症的治疗靶点。这种创新方法的结果应该揭示严重脓毒症中细胞死亡的机制，并开辟一条用抑制 PKR 的药物预防细胞死亡的途径。