The Role and Mechanisms of Lipid and Lipoprotein Dysregulation in Sepsis

脓毒症中脂质和脂蛋白失调的作用和机制

基本信息

批准号：
10382511
负责人：
Faheem W Guirgis
金额：
$ 5万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10382511
关键词：
Anti-Inflammatory Agents Antioxidants Bacterial Toxins Biological Blood Circulation Cessation of life Cholesterol Chronic Clinical Communities Cost Savings Critical Illness Data Disease Drops Enrollment Exhibits Failure Foundations Functional disorder Gender Gene Expression Genomics High Density Lipoproteins Homeostasis Hospitals Impairment Infection Inflammation Inflammatory Lipids Lipoproteins Low-Density Lipoproteins Messenger RNA Metabolism Mission Morbidity - disease rate National Institute of General Medical Sciences Organ Organ failure Outcome Patient Readmission Patients Play Principal Investigator Publishing Reactive Oxygen Species Recovery Research Resolution Risk Role Sampling Sepsis Severities Site Steroid biosynthesis Steroids Survivors Testing Time Toxin biological research clinically relevant cohort evidence base experience hospital readmission lipidomics lipoprotein cholesterol mortality novel oxidation programs prospective recidivism response septic patients

项目摘要

Program Director/Principal Investigator : Guirgis, Faheem Wagid Sepsis is a dysregulated response to infection that has both fatal and non-fatal morbid consequences. Unfortunately, initial survival does not provide relief from morbidity for most sepsis survivors. Initial clinical trajectories include rapid recovery, early in-hospital death, and progression to chronic critical illness (ICU stay ≥ 14 days with organ dysfunction). Late complications include sepsis readmission and late death, both of which have rates of approximately 40% at 90 days and 6 months, respectively. Circulating lipids play an important role in sepsis and cholesterol levels of both high density lipoproteins (HDL-C) and low density lipoproteins (LDL-C) are dynamically regulated in sepsis. HDL and LDL are both thought to play protective roles in sepsis via several mechanisms (antioxidant/anti-inflammatory function, bacterial toxin clearance, steroid synthesis), but the exact mechanisms by which HDL and LDL protects against sepsis are not known. Lipid and lipoprotein dysregulation occurs in early sepsis, leading to failure to protect against sepsis. We have shown that: 1) HDL becomes dysfunctional (pro-oxidant and pro-inflammatory) in early sepsis (Dys-HDL); 2) elevated Dys-HDL levels positively correlate with and predict organ failure severity and are associated with poor outcomes including 28-day mortality; 3) HDL from older septic patients exhibits impaired cholesterol efflux capacity (required for toxin clearance and steroidogenesis); 4) HDL and LDL levels drop precipitously during sepsis, and the severity of the drop is predictive of death; and 5) low baseline LDL levels are associated with increased long-term community-acquired sepsis risk. Highly biologically active lipid metabolites are also present in the circulation during sepsis that may propagate and promote inflammation resolution and contribute to cholesterol dysfunction. Our data strongly suggest that lipid and lipoprotein dysregulation occurs in sepsis and leads to altered function, oxidation, and reduced levels that may influence clinical outcomes. We hypothesize that specific functional, lipidomic, and genomic changes in lipid and lipoprotein metabolism occur in early sepsis and relate to relevant clinical trajectories (rapid recovery, early death, and chronic critical illness and sepsis recidivism). To test our hypothesis, we will capitalize on an established and experienced sepsis research team and the opportunity provided by an existing bank of samples from a diverse cohort of 80 community-acquired (CA) and 85 hospital-acquired (HA) sepsis patients from two-centers. This approach has several advantages: 1) cost-savings from use of existing samples with isolated mRNA, 2) a recent cohort of sepsis patients (2016-2018) consistently treated with institutional evidence-based management bundles, 3) availability of serial samples over time (enrollment, 48h, 28d, and 90d), sepsis readmission samples, and mRNA for the CA cohort, 4) age/gender matched control samples, 5) available clinical and outcomes data. We also propose two-site prospective enrollment of a small cohort of sepsis readmission patients to study this novel and important outcome. This project satisfies the NIGMS mission of researching biological mechanisms that underlay the foundation for advances in treatment of diseases such as sepsis. OMB No. 0925-0001/0002 (Rev. 01/18 Approved Through 03/31/2020) Page Continuation Format Page

计划总监/首席研究员：Guirgis，Faheem Wagid 败血症是对感染的失调反应，既有致命的和非致命的垂死后果。不幸的是，最初的生存并不能减轻大多数败血症生存的发病率。最初的临床轨迹包括快速康复，早期院内死亡以及慢性危害疾病的进展（ICU停留≥ 器官功能障碍14天）。晚期并发症包括败血症再入院和晚期死亡，这两个在90天和6个月时，比率约为40％。循环脂质发挥重要作用高密度脂蛋白（HDL-C）和低密度脂蛋白的败血症和胆固醇水平的作用（LDL-C）在败血症中动态调节。 HDL和LDL都被认为在败血症中扮演保护角色通过几种机制（抗氧化剂/抗炎功能，细菌毒素清除率，类固醇合成），但是，尚不清楚HDL和LDL预防败血症的确切机制。脂肪和脂蛋白失调发生在早期败血症中，导致无法预防败血症。我们已经表明：1）HDL在早期败血症（DYS-HDL）中变得功能失调（促氧化剂和促炎性）； 2）升高的dys-HDL水平与器官失效的严重程度正相关，并与不良结果，包括28天死亡率； 3）老年患者的HDL表现出胆固醇外排受损能力（毒素清除和类固醇生成所需的能力）； 4）HDL和LDL水平在败血症，下降的严重程度可以预测死亡。 5）低基线LDL水平与长期社区获得的败血症风险增加。高度生物活性的脂质代谢产物也是败血症期间的循环中存在，可以传播和促进注射分辨率并贡献胆固醇功能障碍。我们的数据强烈表明脂肪和脂蛋白失调发生在脓毒症中并导致功能，氧化和降低水平的改变，从而影响临床结果。我们假设发生脂质和脂蛋白代谢的特定功能，脂质组和基因组变化在早期败血症中，与相关的临床轨迹有关（快速康复，早死亡和慢性疾病和败血症累犯）。为了检验我们的假设，我们将利用已建立且经验丰富的败血症研究团队以及来自80人群的潜水员队列的现有样品银行提供的机会来自两个中心的社区获得者（CA）和85例医院经验（HA）败血症患者。这种方法有几个优点：1）利用与孤立mRNA的现有样品的使用，2）最近的同类败血症患者（2016-2018）始终接受机构循证管理束的治疗，3）随着时间的推移（注册，48h，28d和90d）的串行样本可用性，败血症再入院样本以及 CA队列的mRNA，4）年龄/性别匹配的对照样本，5）可用的临床和结果数据。我们同样提出了一小部分败血症再入院患者的两点预期入学新颖而重要的结果。该项目满足研究生物学机制的纽格斯任务这奠定了治疗败血症等疾病治疗的基础。 OMB No. 0925-0001/0002（修订版01/18通过03/31/2020批准）页面延续格式页面