Novel Mechanisms and Approaches to Treat Neonatal Sepsis

描述(申请人提供)：每年有一百万名新生儿死于败血症。根据出生体重和败血症发病年龄的不同，这些儿童的死亡率从10%到40%不等，但在极低出生体重儿(VLBW)中死亡率尤其高。人们对新生儿与年轻人有何不同知之甚少，因此，治疗机会有限，而且往往基于针对成年人的治疗。根据我们已发表的和初步的观察，我们的主要观点是，由于早期先天免疫反应中适配器信号的不同，新生儿感染败血症所致器官损伤和死亡的风险更大。更具体地说，我们认为导致CXCL10下游产物的TRIF信号在新生儿中是有缺陷的，新生儿对脓毒症的存活受到这些信号通路缺陷的不利影响。我们的具体目标是(1)确定TRIF依赖的信号通路在新生儿和成年小鼠败血症中的重要性，(2)确定TRIF依赖的CXCL10产物在小鼠新生儿败血症中的作用，以及(3)确定TRIF和CXCL10信号通路作为治疗小鼠新生儿败血症的“靶点”。我们将使用我们开发和验证的多菌腹膜炎(脓毒症)新生小鼠模型，并通过遗传学(TRIF-/-，MyD88-/-基因敲除)和药理学方法评估TRIF信号和CXCL10的重要性。产后4-7天的小鼠(新生)和5-7周龄的小鼠(幼年)会诱发败血症。在某些情况下，TRIF和MyD88信号通路将通过使用基因敲除小鼠来消除，并将评估这些信号通路对CXCL10产生和抗菌反应的依赖性。同样，我们将从药理上阻断CXCL10的活性。另一种方法是使用TLR激动剂和CXCL10作为多菌败血症新生小鼠的佐剂，并评估结果和抗菌反应。这些研究将有助于更好地从根本上了解新生儿对败血症的反应，并阐明可能用于增强新生儿反应的可能途径。重要的是，这项申请针对多个“2010年健康人”目标，以降低与败血症相关的婴儿发病率和死亡率，并可能导致发现新的治疗方法，提高这些特别敏感儿童的存活率。

DESCRIPTION (provided by applicant): One million newborn children die each year from sepsis. Mortality rates among these children range from 10-40% depending on birth weight and age at onset of sepsis, but are especially high in very low birth weight infants (VLBW). Very little is known about how neonates differ from young adults, and thus, therapeutic opportunities are limited and often based on therapies meant for adults. Based on our published and preliminary observations, our central belief is that the neonate has greater risk to sepsis- induced organ injury and mortality because of differences in adaptor signaling in the early innate immune response. More specifically, we propose that TRIF signaling leading to downstream CXCL10 production is defective in neonates, and that neonate survival to sepsis is adversely affected by these defective signaling pathways. Our specific aims are to (1) characterize the importance of TRIF-dependent signaling in neonatal versus adult murine sepsis, (2) determine the role of TRIF-dependent CXCL10 production in murine neonatal sepsis, and, (3) identify the role of TRIF and CXCL10 signaling pathways as a 'target' for therapeutic modality for murine neonatal sepsis. We will use a neonatal mouse model of polymicrobial peritonitis (sepsis) that we have developed and validated, and evaluate the importance of TRIF signaling and CXCL10 through both genetic (TRIF-/-, MyD88-/- knockouts) and pharmacologic approaches. Post-partum day 4-7 mice (neonate) and 5-7 week old mice (young adult) will have sepsis induced. In some cases, TRIF and MyD88 signaling pathways will be eliminated by using knockout mice and the dependence of these pathways on CXCL10 production and antimicrobial responses will be evaluated. Similarly, we will block CXCL10 activity pharmacologically. The alternative approach will be to use TLR agonists and CXCL10 as an adjuvant for neonatal mice subjected to polymicrobial sepsis, and evaluate outcomes and antimicrobial responses. These studies will lead to a better fundamental understanding of the neonatal response to sepsis and elucidate possible pathways that may be used to augment neonatal responses. Importantly, this application addresses multiple "Healthy People 2010" objectives to reduce infant morbidity and mortality related to sepsis, and may lead to the discovery of novel therapeutics that will enhance the survival of these particularly susceptible children.