The Role of Dysfunctional HDL in Sepsis

项目负责人/主要研究者（最后，第一，中间）：Guirgis，Faheem，W 博士Guirgis的长期职业目标是成为一名独立的临床科学家，拥有设计和 实施最高质量的临床和转化研究，以开发个性化的 治疗败血症和其他急性疾病。这项研究计划的长期目标是描述 脓毒症患者病态长期结局的前因和介导因素。尽管成功的早期 脓毒症是一种慢性危重病（CCI -重症监护病房住院≥ 器官功能障碍14天）和病态长期结局（1年时功能依赖或死亡）， 这在早期幸存者中经常发生。既能快速识别有病态结局风险的患者， 新疗法的开发对于改善脓毒症后的结果至关重要。高密度 脂蛋白（HDL）通过以下方式防御脓毒症相关的器官损伤：1）中和细菌内毒素，2） 调节先天性细胞免疫并防止炎性细胞因子的释放，和3）防止 内皮细胞活化和功能障碍。然而，HDL可以成为功能失调（Dys-HDL）， 失去了保护功能，变成了促炎性的。我们的初步结果 表明Dys-HDL存在于早期脓毒症中，并且持续的Dys-HDL升高（最初48小时） 与不良结局（死亡、临终关怀或疗养院护理）相关。本提案的总体目标是 研究并充分描述Dys-HDL在不同CA患者人群中的作用， HA败血症这项研究的中心假设是，HDL的结构和功能变化， 脓毒症与持续存在的Dys-HDL以及炎症和内皮细胞 导致急性器官功能障碍、CCI和病态长期结局的功能障碍。为了验证这一点，我们 在一项双中心、前瞻性、纵向、队列研究中招募160名患者。 在拟议的K奖期间（5年），Guirgis博士将在导师的帮助下发展和 加强他作为翻译研究人员的技能，同时调查Dys-HDL在以下方面的作用： 败血症为了实现作为临床研究人员的独立性，Guirgis博士计划：1）获得实践经验， 临床研究的设计和进行，2）在临床和翻译教学课程 研究，3）接受转化研究技术的培训和教育，重点是脂质生物学， 氧化应激，高密度脂蛋白生理学和炎症生物学，4）提高他作为一个学者的地位 急诊医生和领导者，5）学习如何成为他人的有效导师。 OMB编号0925-0001/0002（2012年8月批准至2015年8月31日修订版）页码续页格式页码

Program Director/Principal Investigator (Last, First, Middle): Guirgis, Faheem, W Dr. Guirgis’ long-term career goal is to become an independent clinician scientist with the skills to design and implement the highest quality clinical and translational research studies to develop individually-tailored treatments for sepsis and other acute diseases. The long-term goal of this research program is to characterize the antecedents and mediators of morbid long-term outcomes in patients with sepsis. Despite successful early management, sepsis is a disease with a high incidence of chronic critical illness (CCI - intensive care unit stay ≥ 14 days with organ dysfunction) and morbid long-term outcomes (functional dependence or death at 1 year), which occur frequently in early survivors. Both the rapid identification of patients at risk for morbid outcomes and the development of novel therapies are crucial for improving outcomes after sepsis. High density lipoprotein (HDL) defends against sepsis-associated organ injury by: 1) neutralizing bacterial endotoxin, 2) modulating innate cellular immunity and preventing release of inflammatory cytokines, and 3) preventing endothelial cell activation and dysfunction. However, HDL can become dysfunctional (Dys-HDL) in the setting of inflammation, losing protective functions and becoming pro-inflammatory. Our preliminary results demonstrate that Dys-HDL is present in early sepsis and that persistent Dys-HDL elevation (first 48 hours) is associated with adverse outcomes (death, hospice or nursing home care). The overall goal of this proposal is to investigate and fully characterize the role of Dys-HDL in a diverse population of patients with both CA and HA-sepsis. The central hypothesis of this study is that structural and functional changes in HDL during sepsis are associated with the persistent presence of Dys-HDL as well as the inflammation and endothelial dysfunction that lead to acute organ dysfunction, CCI, and morbid long-term outcomes. To test this, we will enroll 160 patients in a two-site, prospective, longitudinal, cohort study. During the proposed K award period (5 years), Dr. Guirgis with the help of his mentors will develop and strengthen his skills as a translational researcher while investigating several aspects of the role of Dys-HDL in sepsis. To achieve independence as a clinical researcher, Dr. Guirgis plans to: 1) receive hands-on experience in the design and conduct of clinical research studies, 2) take didactic coursework in clinical and translational research, 3) receive training and education in translational research techniques, focusing on lipid biology, oxidative stress, HDL physiology, and inflammation biology, 4) improve his standing as an academic emergency physician and leader, and 5) learn how to become an effective mentor to others. OMB No. 0925-0001/0002 (Rev. 08/12 Approved Through 8/31/2015) Page Continuation Format Page