The Role of Dysfunctional HDL in Sepsis

HDL 功能障碍在脓毒症中的作用

• 批准号: 9355200
• 负责人: Faheem W Guirgis
• 金额: $ 18.06万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-23 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9355200
• 关键词: Acute; Acute Disease; Anti-Inflammatory Agents; Anti-inflammatory; Antioxidants; Apolipoprotein A-I; Arylesterase; Biological Assay; Biological Markers; Biology; CCL2 gene; Cells; Cellular Immunity; Cessation of life; Chronic; Clinical; Clinical Data; Clinical Research; Clinical Trials; Communities; Critical Illness; Data; Dependence; Development; Disease; E-Selectin; Emergency Department Physician; Endothelial Cells; Endotoxins; Enrollment; Enzymes; Functional disorder; Goals; Grant; High Density Lipoproteins; Home Nursing Care; Hospitals; Hour; Incidence; Individual; Inflammation; Inflammatory; Injury; Intensive Care Units; Intercellular adhesion molecule 1; Interleukin-10; Interleukin-6; K-Series Research Career Programs; Knowledge; Lead; Learning; Lipids; Longitudinal cohort study; Measures; Mediator of activation protein; Mentors; Multiple Organ Failure; Natural History; Organ; Organ failure; Outcome; Oxidative Stress; Patients; Perioperative Nursing; Peroxidases; Physiology; Plasma; Play; Population Heterogeneity; Principal Investigator; Recovery; Research; Research Infrastructure; Research Personnel; Research Technics; Resuscitation; Risk; Role; Scientist; Sepsis; Site; Survivors; TNF gene; Testing; Training and Education; Translational Research; adverse outcome; base; career; clinical application; cytokine; design; endothelial dysfunction; experience; functional status; high density lipoprotein-2; hospice environment; improved; improved outcome; in vivo; individualized medicine; mortality; novel; novel therapeutics; patient population; peptidomimetics; prevent; programs; prospective; reconstitution; research study; screening; skills; translational scientist

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

项目总监/首席调查员（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临床科学家，具有设计和设计技能 实施最高质量的临床和翻译研究以开发单独量身定制的研究 败血症和其他急性疾病的治疗方法。该研究计划的长期目标是表征 败血症患者的病态长期结局的先例和介体。尽管很早就成功了 管理，败血症是一种疾病，患有慢性疾病的发病率很高（CCI - 重症监护病房≥ 器官功能障碍的14天和病态的长期结局（1年的功能依赖或死亡）， 在早期生存中经常发生。两者都快速识别患病风险的患者 新型疗法的发展对于改善败血症后的结局至关重要。高密度 脂蛋白（HDL）通过：1）中和细菌内毒素抗败血症相关器官损伤，2） 调节先天细胞免疫并防止炎症细胞因子释放，3）防止 内皮细胞激活和功能障碍。但是，HDL可以在设置中变功能失调（DYS-HDL） 炎症，失去受保护的功能和促炎。我们的初步结果 证明Dys-HDL存在于早期的败血症中，并且持续的DYS-HDL高程（前48小时）为 与不良结果（死亡，临终关怀或护士家庭护理）相关。该提议的总体目标是 调查并充分表征DYS-HDL在CA和CA和 ha-sepsis。这项研究的中心假设是HDL期间的结构和功能变化 败血症与Dys-HDL的持续存在以及注射和内皮有关 导致急性器官功能障碍，CCI和病态的长期结局的功能障碍。为了测试这一点，我们将 在两次前瞻性，纵向，队列研究中注册160名患者。 在拟议的K奖颁奖期（5年）期间，吉尔吉斯博士在导师的帮助下将发展和 在调查dys-hdl在 败血症。为了获得临床研究人员的独立性，Guirgis博士计划：1） 临床研究的设计和行为，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，HDL生理学和炎症生物学，4）提高他作为学术的地位 急诊医师和领导者，以及5）学习如何成为他人的有效心理。 OMB No. 0925-0001/0002（Rev. 08/12批准通过8/3​​1/2015）页面延续格式页面