Death Receptors in Sepsis

描述（由申请人提供）：项目概述：脓毒症是一种危及生命的疾病，是重症监护病房的主要死亡原因，由革兰氏阴性和/或革兰氏阳性细菌或这些细菌的产物引起。感染导致模式识别受体如toll样受体（TLR）家族的激活，导致促炎细胞因子如白介素-1 B（IL-1 B）和肿瘤坏死因子-a（TNF α）的表达。过去几十年的大量研究表明，过度炎症是脓毒症高死亡率的原因，这导致了几项抗炎策略的临床试验，以降低脓毒症的死亡率。除了活化蛋白C外，这些试验都失败了。细菌还可以直接通过TLR或通过引起死亡受体（DR）的二次激活来诱导几个器官中的凋亡性细胞死亡。该授权申请的假设指出，脓毒症中的多器官衰竭（MOF）是由于器官内的细胞凋亡而发生的，并且细胞死亡是由通过DR和TLR的死亡信号传导诱导的。我们将通过5个具体目标来研究这个假设。1)探讨显性负性Fas相关死亡结构域（FADD-dn）蛋白的过表达是否能改善盲肠结扎穿孔（CLP）诱导的严重脓毒症患者的生存率。2)使用骨髓嵌合体确定造血和非造血Fas在CLP后脓毒症中的作用。3)使用骨髓嵌合体确定CLP后脓毒症中造血细胞与非造血细胞中TLR/MyD 88依赖性信号传导的贡献。4)研究Fas和MyD 88双缺失是否改变CLP后严重脓毒症患者的生存率。5)研究CLP诱导严重脓毒症后肠上皮细胞或心肌细胞中过表达FADD-dn或来自杆状病毒的半胱天冬酶抑制剂p35蛋白的影响。相关性：严重的细菌感染可导致危重患者死亡，并且在美国需要改进的治疗方法来治疗这一主要健康问题。该项目将有助于我们了解死亡原因，并可能提出新的治疗方法。

DESCRIPTION (provided by applicant): Project Summary: Sepsis is a life-threatening condition, the leading causes of death in intensive care units and is caused by Gram-negative and/or Gram-positive bacteria or the products of these bacteria. The infections result in activation of pattern recognition receptors such as the toll-like receptor (TLR) family leading to expression of the pro-inflammatory cytokines such as interleukin-1 b (IL-1b) and tumor necrosis factor-a (TNFa). Considerable research over the past several decades suggested that hyper-inflammation was the cause of high mortality in sepsis and this led to several clinical trials of anti-inflammatory strategies in an effort to reduce the mortality in sepsis. These trials all failed with the exception of activated protein-C. Bacteria can also induce apoptotic cell death in a several organs either directly through TLRs or by causing secondary activation of death receptors (DRs). The hypothesis of this grant application states that multiple organ failure (MOF) in sepsis occurs as a result of apoptosis within the organ and cell death is induced by death signaling through DRs) and TLRs. We will investigate this hypothesis through 5 specific aims. 1) To determine whether over-expression of a dominant negative Fas Associated Death Domain (FADD-dn) protein can improve survival in severe sepsis induced by cecal ligation and puncture (CLP). 2) To determine the contribution of hematopoietic and non-hematopoietic Fas in sepsis following CLP using bone marrow chimeras. 3) To determine the contribution of TLR/MyD88-dependent signaling in hematopoietic versus non-hematopoietic cells in sepsis following CLP using bone marrow chimeras. 4) To examine whether double deletion of Fas and MyD88 alters survival in severe sepsis following CLP. 5) To examine the effect of over-expressing FADD-dn or the caspase inhibitor p35 protein from baculo-virus in intestinal epithelial cells or in cardiomyocytes following induction of severe sepsis by CLP. Relevance: Severe bacterial infection can lead to death in critically ill patients and there is a need for improved thereaputics to treat this major health problem in the United States. This project will aid in our understanding of the cause of death and may suggest new therapies.