The Role and Mechanisms of Lipid and Lipoprotein Dysregulation in Sepsis

方案主任/首席调查员：吉尔吉斯，法希姆·瓦吉德 败血症是一种对感染的失调反应，既有致命的也有非致命的病态后果。 不幸的是，最初的存活期并不能缓解大多数败血症幸存者的并发症。初期临床 轨迹包括快速恢复、早期住院死亡和进展为慢性危重疾病(ICU Stay≥ 14天有器官功能障碍)。晚期并发症包括败血症复发和晚期死亡，这两种情况 90天和6个月的利率分别约为40%。循环中的血脂起着重要的作用 高密度脂蛋白和低密度脂蛋白在脓毒症和胆固醇水平中的作用 (低密度脂蛋白-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到保护作用 通过几种机制(抗氧化/抗炎功能、细菌毒素清除、类固醇合成)， 但高密度脂蛋白和低密度脂蛋白预防脓毒症的确切机制尚不清楚。 脂类和脂蛋白的失调发生在脓毒症的早期，导致对脓毒症的预防失败。我们的 已发表的研究表明，在脓毒症患者中：1)高密度脂蛋白被氧化，成为促炎和 功能障碍；2)功能障碍的高密度脂蛋白与器官衰竭的严重程度相关并可预测；3)高密度脂蛋白胆固醇 与老年败血症患者相比，老年败血症患者的外排功能(毒素清除和类固醇合成所需)受损 健康的老年对照组；4)高密度脂蛋白和低密度脂蛋白水平急剧下降，下降的严重程度预示着器官衰竭 5)低密度脂蛋白水平与长期脓毒症风险增加有关。新的初步数据 在这项拨款修订中还表明，PON1，一种与高密度脂蛋白相关的抗氧化蛋白，可能在 在脓毒症中的保护作用。 我们对脓毒症的脂质和脂蛋白失调的认识存在很大差距，从而阻止完全 了解以前观察到的血脂变化。我们假设炎症性、脂溢性和 早期脓毒症的基因组改变导致脂和脂蛋白代谢紊乱和脂类改变 功能、氧化和降低水平在脓毒症的病理生物学中起着核心作用。 这一新的研究员R01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、Jacksonville和UF)的不同队列的生物库样本 盖恩斯维尔)，并将在一个小的前瞻性队列中确认发现。这种方法有几个优点：1) 最近使用循证管理捆绑包治疗的败血症患者队列(2016-2018)，2)可用性 系列样本(登记、48-72小时、28天和90天)和存储的白细胞mRNA，3)来自匹配的样本 健康对照受试者，4)详细的临床和结果数据，以及5)小队列的预期登记 对脓毒症患者的检查结果进行验证。该项目满足了NIGMS生物学研究的使命 为败血症等疾病的治疗进展奠定基础的机制。 OMB编号0925-0001/0002(01/18修订版批准至2020年3月31日)页面续格式页面

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