PCSK9 and Pediatric Sepsis-Related MODS

PCSK9 和儿科脓毒症相关 MODS

• 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
• 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

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.

摘要 此R21探索性赠款是响应资助机会的重新提交申请 公告号PAR-16-195，“研究，以促进理解和管理的 儿童多器官功能障碍综合征。感染性休克是儿科常见的疾病， 重症监护室和多器官功能障碍综合征（MODS）的最常见原因之一。它 因此，更好地理解儿科特异性感染性休克生物学将有助于更好地理解 小儿多器官功能障碍综合征前蛋白转化酶枯草杆菌蛋白酶/kexin 9型（PCSK 9）在清除 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， 最近的研究探索了PCSK 9在脓毒症中的作用。在脓毒症成人中，PCSK 9功能丧失 突变与提高生存率有关。这一临床观察结果在实验中得到了证实。 脓毒症，其中PCSK 9的遗传消融或药理学抑制在成年小鼠中赋予保护作用 感染了多种微生物败血症这提出了利用PCSK 9抑制作为一种治疗方法的有趣的可能性。 脓毒症的新治疗策略。FDA批准的PCSK 9抑制剂的可用性进一步提高了 对这种方法感兴趣。我们对400多名感染性休克儿童进行了基因分型， 结果.在感染性休克儿童中，PCSK 9功能缺失突变与以下因素独立相关： 即使在调整了疾病严重程度和年龄之后，不良结局的风险也会增加。新的重新提交， 我们现在报道，幼年PCSK 9基因缺失小鼠在多微生物败血症后的死亡率较高， 野生型小鼠。我们现在还表明，未成熟肝脏的炎症反应是显着的， 与成人肝脏不同。这些结果支持了我们长期以来的观点，即新型脓毒症 基于成人和成人实验模型的研究开发的疗法可能不是生物学上的， 适合于儿童，反映了发育对宿主对脓毒症反应的强烈影响。这些 结果还提供了进行儿科宿主特有的机制研究的机会， 直接考虑发育对宿主对脓毒症反应的影响，因此， 儿科MODS这是我们建议的重点。使用幼年模型，我们诱导多微生物 脓毒症在14日龄的小鼠幼崽，我们提出了两个具体的目标。在具体目标1中，我们将检验假设 PCSK 9的抑制在多微生物败血症的幼年模型中是有害的。本目标将利用 PCSK 9缺失小鼠和中和抗PCSK 9抗体。在具体目标2中，我们将检验以下假设： PCSK 9在多微生物脓毒症幼年模型中增加肝脏炎症本目标将利用 LDL受体缺失小鼠和氯化钆介导的枯否细胞耗竭。总的来说，这些研究 本研究旨在阐明PCSK 9在儿童脓毒症中的作用，并阐明脓毒症的一种新机制 儿科宿主特有的生物学