The Role of the Inflammasome in Neonatal Sepsis

炎症小体在新生儿败血症中的作用

• 批准号: 8641708
• 负责人: James Lawrence Wynn
• 金额: $ 17.49万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8641708
• 关键词: Address; Adult; Affect; Agonist; Attenuated; B-Lymphocytes; Biological Markers; Blood Proteins; Caspase-1; Cessation of life; Child; Chronic; Data; Defect; Dendritic Cells; Dependence; Developed Countries; Development; Diagnosis; Employee Strikes; Exhibits; Failure; Fatal Outcome; Fellowship; Foundations; Genetic; Goals; Growth; Human; Immune; Immune response; Immune system; Immunoglobulin Therapy; Immunoglobulins; Immunotherapy; Infection; Inflammatory Response; Interleukin-1; Interleukin-18; Intravenous Immunoglobulins; Investigation; Knock-in Mouse; Knockout Mice; Knowledge; Lead; Life; Link; Mediating; Medical; Mission; Modeling; Morbidity - disease rate; Multicenter Trials; Mus; NADPH Oxidase; National Institute of General Medical Sciences; Natural Immunity; Neonatal; Neonatology; Newborn Infant; Outcome; Pathway interactions; Physicians; Plasma; Predisposition; Pregnancy; Premature Infant; Prevention; Production; Prophylactic treatment; Proteins; Proteomics; Research; Role; Saline; Scientist; Sepsis; Septic Shock; Septicemia; Serum; Signal Pathway; Signal Transduction; Staging; Structure; Systemic infection; T-Lymphocyte; TLR4 gene; TLR8 gene; Testing; Time; Toll-like receptors; Training; Transgenic Organisms; Up-Regulation; antimicrobial; antimicrobial drug; clinically relevant; cytokine; disability; disease diagnosis; high risk; immune function; improved; improved functioning; mRNA Expression; monocyte; mortality; neonatal sepsis; neonate; neutrophil; next generation; novel; novel therapeutic intervention; prevent; public health relevance; pup; receptor; response; septic; transcriptomics; young adult

DESCRIPTION (provided by applicant): Neonatal sepsis is one of the most difficult and costly problems to treat and prevent. Despite antimicrobial therapy, 39% of neonates with sepsis die or suffer major chronic morbidity. Investigations of the neonatal-host immune response to sepsis and its impact on poor long-term outcomes have lagged behind older children and adults. During my fellowship training I developed and validated a clinically-relevant neonatal murine model of polymicrobial sepsis to analyze the neonatal-specific immune response to sepsis-causing agents. We found that neonates exhibit an attenuated innate immune response and are more susceptible to sepsis compared to young adults. Specifically, septic murine neonates produced up to 60 times less IL-1¿ than adults. IL-1¿ production, critical for innate immune cellular function, is intimately linked to inflammasome function. Therefore, we propose to explore the role of inflammasome signaling during murine neonatal sepsis using transgenic knockout mice lacking key inflammasome components. Next, we will determine the differences between neonates and adults in upstream and downstream inflammasome signaling (inflammasome-specific mRNA expression and protein production) following activation of innate immunity receptors (TLRs). Lastly, we will determine the role of enhanced inflammasome activation (using a genetic knock-in humanized mouse) or administration of its mature (active) products (IL-1¿, IL-18) as potential therapies for neonatal sepsis. Cumulatively, we will search for hitherto unknown features of inflammasome development during ontogeny and generate new knowledge about currently poorly understood parameters of the neonatal sepsis through determination of the role of inflammasome signaling. Thus, determining the impact of specific deficiencies in inflammasome components on neonatal vs. adult sepsis and providing direct proof about their potential importance in the susceptibility to and outcome of neonatal sepsis will represent major advance in this research front. Moreover, this investigation will help in the development of much needed biomarkers for neonatal sepsis susceptibility and identification of novel targets for therapy, such as inflammasome gain-offunction immunotherapy directed at improving sepsis outcomes. We will identify the differences in inflammasome signaling intermediates that result in the large discrepancy in IL-1¿ production between septic neonates and adults. Identification of mechanism(s) behind this large difference will allow development of targeted approaches that may lead to improved outcomes. We will thus explore the potential for translational value of inflammasome activation or for provision of its mature products as novel immunotherapies for neonatal sepsis in the aftermath of the negative outcome of intravenous immunoglobulin therapy for neonatal sepsis in a recent multicenter trial (NEJM 2011). We surmise that our focus on one of the most challenging problems in neonatology is consistent with the NIGMS' strategic mission to develop the foundation for advances in disease diagnosis, treatment and prevention as well as development of the next generation of physician-scientists.

描述（由申请人提供）：新生儿败血症是治疗和预防最困难和最昂贵的问题之一。尽管有抗菌治疗，39%的新生儿败血症死亡或遭受重大的慢性发病率。脓毒症的宿主免疫反应及其对不良长期结局的影响的研究落后于年龄较大的儿童和成人。在我的奖学金培训期间，我开发并验证了一种临床相关的新生鼠多微生物败血症模型，以分析对败血症病原体的肠道特异性免疫反应。我们发现，新生儿表现出减弱的先天免疫反应，更容易感染败血症相比，年轻的成年人。具体来说，败血症小鼠新生儿产生的IL-1比成年小鼠少60倍。IL-1的产生对先天免疫细胞功能至关重要，与炎性小体功能密切相关。因此，我们建议使用缺乏关键炎性小体成分的转基因敲除小鼠来探索炎性小体信号传导在小鼠新生败血症中的作用。接下来，我们将确定先天免疫受体（TLR）激活后新生儿和成人之间上游和下游炎性小体信号传导（炎性小体特异性mRNA表达和蛋白质产生）的差异。最后，我们将确定增强炎性小体激活（使用基因敲入人源化小鼠）或给予其成熟（活性）产物（IL-1、IL-18）作为新生儿败血症的潜在治疗方法的作用。累积起来，我们将寻找迄今为止未知的特征，在个体发育过程中的炎性小体的发展，并通过确定炎性小体信号传导的作用，产生新的知识，目前了解甚少的新生儿败血症的参数。因此，确定炎性体组分的特定缺陷对新生儿与成人脓毒症的影响，并提供关于其在新生儿脓毒症易感性和结局中的潜在重要性的直接证据，将有助于确定新生儿脓毒症的发病机制。 代表了这一研究前沿的重大进展。此外，这项研究将有助于开发急需的新生儿脓毒症易感性生物标志物，并确定新的治疗靶点，如旨在改善脓毒症结局的炎性小体获得功能免疫治疗。我们将找出不同之处， 炎症体信号中间体，导致脓毒症新生儿和成人之间IL-1？产生的巨大差异。查明这一巨大差异背后的机制将有助于制定有针对性的办法，从而可能导致更好的结果。因此，我们将探索炎性小体激活的转化价值或提供其成熟产物作为新生儿败血症的新型免疫疗法的潜力，在最近的一项多中心试验中，静脉注射免疫球蛋白治疗新生儿败血症的结果为阴性（NEJM 2011）。我们相信，我们对肿瘤学中最具挑战性的问题之一的关注与NIGMS的战略使命是一致的，即为疾病诊断、治疗和预防以及下一代医生科学家的发展奠定基础。