The Role and Mechanisms of Lipid and Lipoprotein Dysregulation in Sepsis

项目主任/主要研究者：Guirgis，Faheem Wagid 脓毒症是一种对感染的失调反应，具有致命和非致命的病态后果。 不幸的是，最初的生存并不能减轻大多数脓毒症幸存者的发病率。初始临床 轨迹包括快速恢复、早期住院死亡和进展为慢性危重病（ICU住院时间≥ 器官功能障碍14天）。晚期并发症包括脓毒症复发和晚期死亡，这两种并发症都是 90天和6个月时的发生率分别约为40%。循环脂质在 高密度脂蛋白（HDL-C）和低密度脂蛋白在脓毒症和胆固醇水平中的作用 （LDL-C）在脓毒症中动态调节。高密度脂蛋白和低密度脂蛋白都被认为在脓毒症中起保护作用 通过几种机制（抗氧化/抗炎功能，细菌毒素清除，类固醇合成）， 但HDL和LDL对抗败血症的确切机制尚不清楚。 脂质和脂蛋白失调发生在早期脓毒症中，导致不能防止脓毒症。我们 已发表的工作表明，在脓毒症患者中：1）HDL被氧化，变成促炎性的， 功能障碍; 2）功能障碍HDL与器官衰竭严重程度相关并预测器官衰竭严重程度; 3）HDL胆固醇 外排（毒素清除和类固醇合成所需）在老年脓毒症患者中受损， 健康老年对照组; 4）HDL-C和LDL-C水平急剧下降，下降严重程度预示器官衰竭 和死亡;和5）低LDL-C水平与长期脓毒症风险增加相关。新的初步数据 在这项拨款修订中还表明，PON 1，一种HDL相关的抗氧化蛋白，可能在 脓毒症的保护作用。 我们对脓毒症中脂质和脂蛋白失调的认识存在很大的差距， 了解以前观察到的脂质变化。我们假设炎症、脂质组学和 早期脓毒症的基因组变化导致脂质和脂蛋白代谢失调&脂质改变 在脓毒症病理生物学中起核心作用的功能、氧化和降低的水平。 这一新的研究者R 01应用程序将允许Guirgis博士进一步建立他的实验室，并将 利用来自165名脓毒症患者（UF杰克逊维尔和UF 盖恩斯维尔），并将在一个小的前瞻性队列中证实研究结果。这种方法有几个优点：1） 近期接受循证管理包治疗的脓毒症患者队列（2016-2018年），2）可用性 连续样本（入组，48- 72 h，28 d和90 d）和储存的白细胞mRNA，3）来自匹配的 健康对照受试者，4）详细的临床和结局数据，以及5）小型队列的前瞻性招募 对败血症患者的研究结果进行验证。该项目满足了NIGMS研究生物学的使命， 这些机制为疾病如败血症的治疗进展奠定了基础。 OMB编号0925-0001/0002（2018年1月批准至2020年3月31日修订版）页码续页格式页码

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