The Role of Dysfunctional HDL in Sepsis

项目总监/首席研究员（最后、第一、中间）：Guirgis、Faheem、W Guirgis 博士的长期职业目标是成为一名独立的临床科学家，具备设计和 实施最高质量的临床和转化研究以开发个性化定制的 败血症和其他急性疾病的治疗。该研究计划的长期目标是表征 脓毒症患者病态长期结局的前因和中介因素。尽管早期取得了成功 管理方面，脓毒症是一种慢性危重病发病率较高的疾病（CCI-重症监护病房住院时间≥ 14 天器官功能障碍）和病态长期结果（功能依赖或 1 岁时死亡）， 这在早期幸存者中经常发生。快速识别有患病风险的患者 新疗法的开发对于改善脓毒症后的预后至关重要。高密度 脂蛋白 (HDL) 通过以下方式防御败血症相关的器官损伤：1) 中和细菌内毒素，2) 调节先天细胞免疫并防止炎症细胞因子的释放，3) 预防 内皮细胞活化和功能障碍。然而，HDL 可能会出现功能障碍（Dys-HDL） 炎症，失去保护功能并变得促炎。我们的初步结果 证明 Dys-HDL 存在于早期脓毒症中，并且持续性 Dys-HDL 升高（前 48 小时）与 与不良后果（死亡、临终关怀或疗养院护理）相关。该提案的总体目标是 调查并充分表征 Dys-HDL 在不同人群的 CA 和 CA 患者中的作用 HA-败血症。本研究的中心假设是 HDL 的结构和功能变化 脓毒症与 Dys-HDL 的持续存在以及炎症和内皮细胞相关 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 名患者参加一项两中心、前瞻性、纵向队列研究。 在拟议的 K 奖期间（5 年），Guirgis 博士在导师的帮助下将发展和 加强他作为转化研究员的技能，同时研究 Dys-HDL 在 败血症。为了实现作为一名临床研究人员的独立性，Guirgis 博士计划：1) 获得以下方面的实践经验： 临床研究的设计和实施，2）参加临床和转化方面的教学课程 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、HDL 生理学和炎症生物学，4) 提高他的学术地位 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（修订版 08/12 已批准至 8/31/2015） 页面延续格式页面

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