High-density lipoprotein (HDL) is key a component of circulating blood and plays essential roles in vascular endothelial cells and immunity. However, the levels of HDL decrease by 40-70% in septic patients, which is associated with a poor prognosis. Using ApoAI null mice as an HDL deficient model, we recently reported that mice lacking HDL are susceptible to cecal ligation and puncture (CLP)-induced septic death, and increase HDL levels by over expression of ApoAI protects CLP-induced septic death. These clinical and animal studies indicate that a decrease in HDL levels is a risk factor for sepsis and raising circulating HDL levels may provide an efficient therapy for sepsis. In the preliminary study, we demonstrated that synthetic HDL (sHDL) treatment significantly protects mice from CLP-induced septic death, indicating that sHDL is a potential effective therapy for sepsis. We hypothesize that sHDL therapy protects sepsis by restoring both HDL level and its immune- and vascular-protective functions. The objectives of this grant are to understand the mechanism(s) underlying sHDL vascular protection, to use this information to tailor the sHDL composition and to optimize treatment strategy specifically for sepsis. To achieve the grant objectives we plan to: 1) determine the mechanisms of sHDL's protection against sepsis-induced vascular pathogenesis; 2) Tailor sHDL composition for increased efficacy in sepsis; and 3) Optimize the sHDL treatment regimen for sepsis and test in immunocompromised septic mice. Completion of this preclinical study will provide a body of mechanistic data for a novel sHDL-based therapeutic approach for treatment of sepsis and position it for rapid clinical translation.

Public Health Relevance

The goal of this application is to develop synthetic HDL for sepsis therapy. We expect that completion of this preclinical study will provide a body of mechanistic data for a novel synthetic HDL-based therapeutic approach for treatment of sepsis and position it for rapid clinical translation.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZHL1)
Program Officer
Dunsmore, Sarah
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Kentucky
Schools of Medicine
United States
Zip Code
Li, Dan; Fawaz, Maria V; Morin, Emily E et al. (2018) Effect of Synthetic High Density Lipoproteins Modification with Polyethylene Glycol on Pharmacokinetics and Pharmacodynamics. Mol Pharm 15:83-96
Zheng, Zhong; Ai, Junting; Guo, Ling et al. (2018) SR-BI (Scavenger Receptor Class B Type 1) Is Critical in Maintaining Normal T-Cell Development and Enhancing Thymic Regeneration. Arterioscler Thromb Vasc Biol 38:2706-2717
Morin, Emily E; Li, Xiang-An; Schwendeman, Anna (2018) HDL in Endocrine Carcinomas: Biomarker, Drug Carrier, and Potential Therapeutic. Front Endocrinol (Lausanne) 9:715
Guo, Yanhong; Yuan, Wenmin; Yu, Bilian et al. (2018) Synthetic High-Density Lipoprotein-Mediated Targeted Delivery of Liver X Receptors Agonist Promotes Atherosclerosis Regression. EBioMedicine 28:225-233
Tang, Jie; Kuai, Rui; Yuan, Wenmin et al. (2017) Effect of size and pegylation of liposomes and peptide-based synthetic lipoproteins on tumor targeting. Nanomedicine 13:1869-1878
Smith, Carolyne K; Seto, Nickie L; Vivekanandan-Giri, Anuradha et al. (2017) Lupus high-density lipoprotein induces proinflammatory responses in macrophages by binding lectin-like oxidised low-density lipoprotein receptor 1 and failing to promote activating transcription factor 3 activity. Ann Rheum Dis 76:602-611
Tang, Jie; Li, Dan; Drake, Lindsey et al. (2017) Influence of route of administration and lipidation of apolipoprotein A-I peptide on pharmacokinetics and cholesterol mobilization. J Lipid Res 58:124-136
Kuai, Rui; Ochyl, Lukasz J; Bahjat, Keith S et al. (2017) Designer vaccine nanodiscs for personalized cancer immunotherapy. Nat Mater 16:489-496
Yuan, Yue; Wen, Jian; Tang, Jie et al. (2016) Synthetic high-density lipoproteins for delivery of 10-hydroxycamptothecin. Int J Nanomedicine 11:6229-6238
Yu, Lawrence X; Akseli, Ilgaz; Allen, Barbara et al. (2016) Advancing Product Quality: a Summary of the Second FDA/PQRI Conference. AAPS J 18:528-43

Showing the most recent 10 out of 17 publications