The Role of Dysfunctional HDL in Sepsis

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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