The Role of Dysfunctional HDL in Sepsis

项目主任/首席调查员(最后、第一、中间)：吉尔吉斯，法希姆，W Guirgis博士的长期职业目标是成为一名独立的临床科学家，拥有设计和开发 实施最高质量的临床和转化性研究以开发个性化定制的研究 脓毒症和其他急性疾病的治疗。这项研究计划的长期目标是 脓毒症患者病态远期结局的影响因素和介体。尽管很早就成功了 管理，败血症是一种慢性危重病(CCI-ICU Stay≥)的高发疾病 器官功能障碍14天)和病态的长期结果(功能依赖或1年内死亡)， 这种情况经常发生在早期幸存者身上。既可以快速识别有病态结局风险的患者 而新疗法的开发对于改善脓毒症的预后至关重要。高密度 脂蛋白(HDL)通过：1)中和细菌内毒素，2)保护败血症相关器官损伤。 调节天然细胞免疫，防止炎症细胞因子的释放，以及3)防止 内皮细胞的激活和功能障碍。然而，在设置中，高密度脂蛋白可能会变得功能失调(Dys-高密度脂蛋白 炎症，失去保护功能，变得促炎。我们的初步结果 证明Dys-高密度脂蛋白在早期脓毒症中存在，持续的Dys-高密度脂蛋白升高(最初48小时)是 与不良后果(死亡、临终关怀或疗养院护理)有关。这项提案的总体目标是 研究并充分描述Dys-高密度脂蛋白在CA和CA患者不同人群中的作用 哈-败血症。这项研究的中心假设是，在高密度脂蛋白的结构和功能变化 脓毒症与Dys-高密度脂蛋白的持续存在以及炎症和内皮细胞有关 导致急性器官功能障碍、CCI和病态长期结果的功能障碍。为了测试这一点，我们将 招募160名患者参加一项两点前瞻性纵向队列研究。 在拟议的K奖励期间(5年)，Guirgis博士将在他的导师的帮助下开发和 加强他作为翻译研究人员的技能，同时研究Dys-HDL在 败血症。为了实现临床研究人员的独立性，Guirgis博士计划：1)在以下方面获得实践经验 临床研究研究的设计和实施，2)参加临床和翻译的教学课程 研究，3)接受翻译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)提高了他作为学者的地位 急诊医生和领导，以及学习如何成为他人的有效导师。 OMB编号0925-0001/0002(08/12版批准至2015年8月31日)页面续格式页面

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