PKR mediated inflammasome activation and pyroptosis in sepsis

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身上的临床综合征，在美国每年的发病率约为75万例。死亡率为20-30%，目前尚无批准用于临床的特定治疗剂。事实上，唯一特别批准的药物（Xigris）最近因疗效不佳而退出临床。尸检研究表明，严重败血症患者的主要细胞死亡机制是程序性细胞死亡，通过两种主要途径，称为“凋亡”和“焦亡”。之前通过阻断炎性小体来防止细胞死亡的努力非常困难，因为直到最近，控制炎性小体的主要调节蛋白的身份仍然未知。然而，一项创新的发现揭示了炎性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《自然》杂志上报道了这一发现，现在它使我们能够通过抑制PKR直接靶向炎性体；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。我们将采用一种创新的新方法来关注严重脓毒症期间的焦亡是有害的这一总体假设，并且通过灭活pkr依赖性炎症小体激活来抑制焦亡将对宿主有益。这将通过三个目标来实现：PKR在焦亡过程中的重要调控作用具体目标2。PKR在炎性小体组装中的作用3.具体目标PKR作为脓毒症的治疗靶点。这一创新方法的结果将揭示严重脓毒症中细胞死亡的机制，并为抑制PKR的药物预防脓毒症开辟一条途径。

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 Indeed, the only specifically approved agent (Xigris) was recently withdrawn from the clinic because of poor efficacy.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.