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：
10591486
负责人：
Faheem W Guirgis
金额：
$ 47.33万
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/10591486
关键词：
Anti-Inflammatory Agents Antioxidants Apolipoproteins Arylesterase Bacterial Toxins Biological Cessation of life Cholesterol Chronic Clinical Critical Illness Data Disease Drops Electrospray Ionization Endothelial Cells Enrollment Enzymes Exhibits Failure Fatty Acids Foundations Functional disorder Gene Expression Genes Genomics Grant HDL(3) Cholesterol Heterogeneity High Density Lipoproteins Homeostasis Hospitals Impairment Infection Inflammation Inflammation Mediators Inflammatory Investigation Knowledge LDL Cholesterol Lipoproteins Laboratories Leukocytes Leukotrienes Lipids Lipoproteins Low Density Lipoprotein oxidation Low-Density Lipoproteins Measures Messenger RNA Metabolic Metabolism Mission Morbidity - disease rate National Institute of General Medical Sciences Organ Organ failure Outcome Oxidative Stress Patient Readmission Patient-Focused Outcomes Patients Pattern Peripheral Blood Mononuclear Cell Peroxidases Physical Function Play Principal Investigator Prospective cohort Prospective, cohort study Prostaglandins Proteins Publishing Quality of life RNA Recovery Research Personnel Risk Role Sampling Sepsis Severities Steroids Survivors T-Lymphocyte Testing Time Toxin Up-Regulation Validation Whole Blood Work biobank cohort cost cytokine evidence base improved inflammatory marker lipid mediator lipid metabolism lipidomics liquid chromatography mass spectrometry monocyte mortality neutrophil novel outcome prediction oxidation oxidized lipid participant enrollment precision medicine predictive signature prevent programs prospective recidivism response reverse cholesterol transport 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 recidivism 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 protect against sepsis are not known. Lipid and lipoprotein dysregulation occurs in early sepsis, leading to failure to protect against sepsis. Our published work has shown that in sepsis patients: 1) HDL is oxidized, becomes proinflammatory and dysfunctional; 2) dysfunctional HDL correlates with and predicts organ failure severity; 3) HDL cholesterol efflux (required for toxin clearance and steroid synthesis) is impaired in older septic patients compared to healthy older controls; 4) HDL-C and LDL-C levels drop precipitously, and drop-severity predicts organ failure and death; and 5) low LDL-C levels are associated with increased long-term sepsis risk. New preliminary data in this grant revision also suggests that PON1, an HDL associated antioxidant protein, may play a critical protective role in sepsis. A large gap in our knowledge of lipid and lipoprotein dysregulation in sepsis exists that prevents complete understanding of previously observed lipid changes. We hypothesize that inflammatory, lipidomic, and genomic changes in early sepsis result in dysregulated lipid and lipoprotein metabolism & altered lipid function, oxidation and reduced levels that play a central role in sepsis pathobiology. This new investigator R01 application will allow Dr. Guirgis to further establish his laboratory and will capitalize on biobanked samples from a diverse cohort of 165 sepsis patients (UF Jacksonville and UF Gainesville) and will confirm findings in a small prospective cohort. This approach has several advantages: 1) recent cohort of sepsis patients (2016-2018) treated with evidence-based management bundles, 2) availability of serial samples (enrollment, 48-72h, 28d, and 90d) & stored leukocyte mRNA, 3) samples from matched healthy control subjects, 4) detailed clinical and outcomes data, and 5) prospective enrollment of a small cohort of sepsis patients for validation of findings. 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累犯和晚期死亡，这两者都在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。我们的已发表的工作表明，在败血症患者中：1）HDL被氧化，促炎和功能失调； 2）功能失调的HDL与器官衰竭严重程度相关并预测； 3）HDL胆固醇与年龄较大的化粪池患者相比健康的较旧对照； 4）HDL-C和LDL-C水平降低精度，并进行落下预测器官故障和死亡； 5）低LDL-C水平与长期败血症风险增加有关。新的初步数据在此赠款中，修订还表明，HDL相关的抗氧化剂蛋白PON1可能起关键败血症的保护作用。我们对败血症中脂质和脂蛋白失调的知识存在很大的差距，可以防止完整了解先前观察到的脂质变化。我们假设这种炎症，脂质组和早期败血症的基因组变化导致脂质和脂蛋白代谢失调和脂质改变功能，氧化和降低水平在脓毒症病理学中起着核心作用。这项新的调查员R01申请将允许Guirgis博士进一步建立他的实验室，并将从165名败血症患者组成的潜水员队列中大写（UF Jacksonville和UF）盖恩斯维尔），并将在一个小的潜在队列中确认发现。这种方法具有几个优点：1）败血症患者的近期队列（2016-2018）接受了基于证据的管理捆绑包，2）可用性系列样品（注册，48-72H，28d和90d）和存储的白细胞mRNA，3）来自匹配的样品健康对照受试者，4）详细的临床和结果数据，以及5）少量队列的预期入学败血症患者的发现。该项目满足研究生物学的刺激性使命为治疗败血症等疾病治疗的基础的机制。 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