PCSK9 and Pediatric Sepsis-Related MODS

PCSK9 和儿科脓毒症相关 MODS

基本信息

批准号：
9756433
负责人：
HECTOR R. WONG
金额：
$ 19.88万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-06 至 2021-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9756433
关键词：
Ablation Adolescent Adult Age Alleles Antibodies Binding Biological Biology Child Childhood Clinical Data Development Drug Metabolic Detoxication Endotoxins Equilibrium Experimental Models FDA approved Functional disorder Funding Opportunities Genes Genetic Genotype Grant Hepatic Hepatocyte IL8 gene Immune response Inflammation Inflammatory Inflammatory Response Injury Interleukin-8 Intraperitoneal Injections Knockout Mice Kupffer Cells Laboratories Link Lipids Lipopolysaccharides Liver Low Density Lipoprotein Receptor Low-Density Lipoproteins Mediating Metabolism Modeling Multiple Organ Failure Mus Mutation Organ Outcome Pediatric Intensive Care Units Pharmaceutical Preparations Pharmacology Plasma Play Proprotein Convertases Public Health Recycling Reporting Research Research Personnel Risk Role Secondary to Sepsis Septic Shock Severity of illness Subtilisins Surface Testing Wild Type Mouse base cytokine experimental study gadolinium chloride gain of function mutation improved improved outcome inhibitor/antagonist interest lipoteichoic acid liver inflammation loss of function loss of function mutation mortality novel novel therapeutics polymicrobial sepsis prevent programs pup response therapy development uptake

项目摘要

ABSTRACT This R21 exploratory grant is a resubmission application in response to the funding opportunity announcement number PAR-16-195, “Research to Advance the Understanding and Management of the Multiple Organ Dysfunction Syndrome in Children”. Septic shock is a prevalent condition in the pediatric intensive care unit and one of the most common causes of multiple organ dysfunction syndrome (MODS). It follows that a better understanding of pediatric-specific septic shock biology will lead to a better understanding of pediatric MODS. Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a major role in clearance of low-density lipoprotein (LDL). Since LDL metabolism is closely linked to clearance of bacterial lipid moieties, recent studies have explored the role of PCSK9 in sepsis. In adults with sepsis, a PCSK9 loss of function mutation is associated with improved survival. This clinical observation was corroborated in experimental sepsis, wherein genetic ablation or pharmacologic inhibition of PCSK9 confers protection in adult mice challenged with polymicrobial sepsis. This raises the intriguing possibility of leveraging PCSK9 inhibition as a novel therapeutic strategy for sepsis. The availability of an FDA approved PCSK9 inhibitor further raises interest in this approach. We genotyped over 400 children with septic shock and found the opposite result. Among children with septic shock, a PCSK9 loss of function mutation is independently associated with increased risk of poor outcome, even after adjusting for illness severity and age. New to this resubmission, we now report that juvenile PCSK9 null mice have a higher mortality rate after polymicrobial sepsis, compared to wild type mice. We also now show that the inflammatory response of the immature liver is dramatically different than that of the adult liver. These results support our long-standing contention that novel sepsis therapies developed based on studies in adults and adult experimental models, might not be biologically appropriate for children, reflecting the strong influence of development on the host response to sepsis. These results also provide an opportunity to conduct mechanistic studies that are unique to the pediatric host and directly consider the influence of development on the host response to sepsis, and hence, the biology of pediatric MODS. This is the focus of our proposal. Using a juvenile model, in which we induce polymicrobial sepsis in 14-day-old mouse pups, we propose two Specific Aims. In Specific Aim 1, we will test the hypothesis that inhibition of PCSK9 is deleterious in a juvenile model of polymicrobial sepsis. This Aim will make use of PCSK9 null mice and a neutralizing anti-PCSK9 antibody. In Specific Aim 2, we will test the hypothesis that PCSK9 augments hepatic inflammation in a juvenile model of polymicrobial sepsis. This Aim will make use of LDL receptor null mice and gadolinium chloride-mediated Kupffer cell depletion. Collectively, the studies propose here will clarify the role of PCSK9 in pediatric sepsis and elucidate a novel mechanism of sepsis biology specific to the pediatric host.

抽象的此 R21 探索性资助是为了响应资助机会而重新提交的申请公告号 PAR-16-195，“促进对环境的理解和管理的研究” 儿童多器官功能障碍综合征”。败血性休克是儿科的常见病症。重症监护病房和多器官功能障碍综合征（MODS）最常见的原因之一。因此，更好地了解儿科特异性感染性休克生物学将有助于更好地理解儿科 MODS 的前蛋白转化酶枯草杆菌蛋白酶/kexin 9 型 (PCSK9) 在清除中发挥重要作用。低密度脂蛋白 (LDL) 由于 LDL 代谢与细菌脂质部分的清除密切相关，最近的研究探讨了 PCSK9 在败血症中的作用。在患有败血症的成人中，PCSK9 功能丧失。突变与生存率的提高相关，这一临床观察结果在实验中得到了证实。脓毒症，提供 PCSK9 的遗传消融或药物抑制，为成年小鼠提供保护面临多种微生物败血症的挑战，这提出了利用 PCSK9 抑制作为治疗方法的有趣可能性。 FDA 批准的 PCSK9 抑制剂的可用性进一步提高了败血症的新治疗策略。我们对 400 多名感染性休克儿童进行了基因分型，发现了相反的结果。结果表明，在感染性休克儿童中，PCSK9 功能丧失突变与感染性休克独立相关。即使在调整了疾病严重程度和年龄后，结果不佳的风险也会增加。我们现在报道，相比之下，幼年 PCSK9 缺失小鼠在多种微生物败血症后死亡率更高我们现在还发现，未成熟肝脏的炎症反应非常显着。与成人肝脏不同，这些结果支持了我们长期以来关于新型败血症的观点。基于成人研究和成人实验模型开发的疗法可能不具有生物学意义适合儿童，反映了发育对宿主对脓毒症反应的强烈影响。结果还提供了进行儿科宿主特有的机械研究的机会直接考虑发育对宿主对脓毒症反应的影响，因此，这是我们建议的重点，我们使用青少年模型诱导多种微生物。针对 14 日龄幼鼠败血症，我们提出了两个具体目标在具体目标 1 中，我们将检验假设。 PCSK9 的抑制对于多种微生物败血症的幼年模型是有害的。 PCSK9 缺失小鼠和中和抗 PCSK9 抗体在特定目标 2 中，我们将检验以下假设： PCSK9 在多种微生物败血症的幼年模型中增强肝脏炎症。 LDL 受体缺失小鼠和氯化钆介导的库普弗细胞耗竭研究。此处提出将阐明 PCSK9 在儿科脓毒症中的作用并阐明脓毒症的新机制儿科宿主特有的生物学。