Novel Mechanisms and Approaches to Treat Neonatal Sepsis

治疗新生儿败血症的新机制和新方法

基本信息

批准号：
8244431
负责人：
LYLE L MOLDAWER
金额：
$ 27.84万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-04-01 至 2015-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8244431
关键词：
Adaptor Signaling Protein Address Adjuvant Adult Affect Age Agonist Area Bacterial Infections Belief Birth Weight CXCL10 gene Cell physiology Characteristics Child Defect Dependence Diagnostic Effector Cell Epidemiology Event Functional disorder Genetic Health Health Status Health Status Indicators Healthy People 2010 Immune Immune response Immune system Immunity Infant Infant Health Infant Mortality Infection Inflammation Injury Interferons Interleukin-1 Receptors Knock-out Knockout Mice Laboratories Lead Lipopolysaccharides Low Birth Weight Infant Measures Modality Morbidity - disease rate Mus Myelogenous Natural Immunity Neonatal Neutrophil Infiltration Newborn Infant Organ Outcome Pathway interactions Perinatal Peritoneum Peritonitis Personal Satisfaction Plasma Population Predisposition Premature Infant Production Proteins Publishing Reactive Oxygen Species Receptor Signaling Regulatory Element Research Risk Role Sepsis Signal Pathway Signal Transduction Site Therapeutic Therapeutic Intervention Toll-like receptors United States Very Low Birth Weight Infant Viral Work adverse outcome antimicrobial base chemokine cytokine improved infant death insight molecular marker mortality mouse model neonatal sepsis neonate next generation novel novel therapeutics public health relevance response social therapeutic target young adult

项目摘要

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. PUBLIC HEALTH RELEVANCE: Newborn infants, especially very low birthweight infants are at increased risk of developing sepsis and dying from it. We propose that this increased susceptibility is due to defects in innate immunity and production of chemokines, particularly CXCL10. Studies are proposed to examine differential adaptor signaling in murine neonatal sepsis, and explore the use of adjuvants that will enhance survival.

描述（由申请人提供）：每年有一百万新生儿死于败血症。这些儿童的死亡率为 10-40%，具体取决于出生体重和败血症发病年龄，但极低出生体重婴儿 (VLBW) 的死亡率尤其高。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，并且通常基于针对成人的治疗。根据我们已发表的初步观察结果，我们的核心观点是，由于早期先天免疫反应中接头信号传导的差异，新生儿因脓毒症引起的器官损伤和死亡的风险更大。更具体地说，我们提出导致下游 CXCL10 产生的 TRIF 信号传导在新生儿中存在缺陷，并且这些缺陷信号传导途径对新生儿脓毒症存活率产生不利影响。我们的具体目标是 (1) 表征 TRIF 依赖性信号传导在新生儿与成年小鼠败血症中的重要性，(2) 确定 TRIF 依赖性 CXCL10 产生在小鼠新生儿败血症中的作用，以及 (3) 确定 TRIF 的作用CXCL10 信号通路作为小鼠新生儿败血症治疗方式的“靶标”。我们将使用我们开发并验证的多种微生物腹膜炎（脓毒症）新生小鼠模型，并通过遗传（TRIF-/-、MyD88-/- 敲除）和药理学方法评估 TRIF 信号传导和 CXCL10 的重要性。产后 4-7 天的小鼠（新生儿）和 5-7 周大的小鼠（年轻的成年小鼠）将诱发败血症。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，并且将评估这些通路对 CXCL10 产生和抗菌反应的依赖性。同样，我们将从药理学上阻断 CXCL10 活性。另一种方法是使用 TLR 激动剂和 CXCL10 作为患有多种微生物败血症的新生小鼠的佐剂，并评估结果和抗菌反应。这些研究将有助于更好地了解新生儿对脓毒症的反应，并阐明可用于增强新生儿反应的可能途径。重要的是，该应用解决了“2010年健康人”的多个目标，以降低与败血症相关的婴儿发病率和死亡率，并可能导致新疗法的发现，从而提高这些特别易感儿童的生存率。公共卫生相关性：新生儿，尤其是出生体重极低的婴儿，患败血症并因此死亡的风险增加。我们认为这种易感性增加是由于先天免疫和趋化因子（特别是 CXCL10）产生的缺陷所致。建议研究检查小鼠新生儿败血症中的差异适配器信号传导，并探索使用可提高存活率的佐剂。