Novel Mechanisms and Approaches to Treat Neonatal Sepsis

描述（由申请人提供）：每年有100万新生儿死于败血症。 这些儿童的死亡率范围为10-40%，具体取决于出生体重和败血症发作时的年龄，但极低出生体重儿（VLBW）的死亡率尤其高。 关于新生儿与年轻人的差异知之甚少，因此，治疗机会有限，通常基于成人的治疗。 基于我们发表的和初步的观察，我们的中心信念是，由于早期先天免疫应答中衔接子信号传导的差异，新生儿具有更大的脓毒症诱导的器官损伤和死亡的风险。 更具体地说，我们认为导致下游CXCL 10产生的TRIF信号传导在新生儿中是有缺陷的，并且新生儿对败血症的存活受到这些有缺陷的信号传导途径的不利影响。我们的具体目标是（1）表征TRIF依赖性信号传导在新生鼠败血症与成年鼠败血症中的重要性，（2）确定TRIF依赖性CXCL 10产生在新生鼠败血症中的作用，以及（3）鉴定TRIF和CXCL 10信号传导途径作为新生鼠败血症治疗方式的“靶标”的作用。 我们将使用我们已经开发和验证的多微生物腹膜炎（败血症）的新生小鼠模型，并通过遗传（TRIF-/-，MyD 88-/-敲除）和药理学方法评估TRIF信号传导和CXCL 10的重要性。产后4-7天的小鼠（新生儿）和5-7周龄的小鼠（年轻成年人）将诱导败血症。 在某些情况下，TRIF和MyD 88信号通路将通过使用敲除小鼠消除，并将评估这些通路对CXCL 10产生和抗微生物应答的依赖性。 同样，我们将阻止CXCL 10活动。 另一种方法是使用TLR激动剂和CXCL 10作为多微生物败血症新生小鼠的佐剂，并评估结果和抗菌反应。 这些研究将导致更好地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，该申请解决了多个“健康人2010”目标，以减少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，这将提高这些特别易感儿童的生存率。

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.