This K08 application is a proposal for the development of the applicant towards scientific independence while performing research to develop novel insights into the pathophysiology of injury-induced immunosuppression and study a novel therapeutic strategy for this syndrome. The applicant will investigate post-injury immunosuppression under the guidance of an advisory committee led by Drs. Edward Sherwood and Frank Schmalstieg. These investigators have each made strong contributions to the fields of sepsis and burn injury, and have committed to providing the applicant with strong mentorship and training in molecular and immunologic experimental techniques. The applicant will also benefit from his unique placement within the Shriners' Burns Institute which provides avenues for collaboration and development of junior investigators through weekly scientific review meetings. Finally, the applicant intends to round out his development with participation in a number of didactic pursuits, including immunology journal clubs and weekly seminars, and post-graduate classes in immunology, flow cytometry, molecular biology. While investigating the innate immune response during an immunosuppressed state, the applicant will acquire new knowledge and skills necessary to develop a strong background in basic and applied immunology. The Dept. of Anesthesiology and the Shriners' Burns Institute at UTMB provide expertise from diverse resources and provide an ideal setting for training scientists. Patient survival after a severe injury or infectious insult has been greatly improved by the capacity of physicians to provide fluid resuscitation and physiological support. However, secondary infection is a major cause of morbidity and mortality in these patients. Post-injury immunosuppression is emerging as a predisposing factor for the development of secondary infection. Our preliminary studies show that dendritic cell and macrophage dysfunction contribute significantly to the state of immunosuppression observed in the critically ill host. The purpose of the proposed research is to further define dendritic cell and macrophage function during the post-injury period and examine the ability of the hemopoietic factor Flt3-L to improve dendritic cell function and resistance to secondary infection.
The specific aims i nclude: 1) Investigating the role that altered dendritic cell function plays in diminished bacterial clearance after cecal ligation and puncture; 2) Determining if Flt3-L expansion of dendritic cells results in increased IL-12 and IFNgamma expression and enhanced resistance to infection; and 3) Investigating the role that altered macrophage function plays in diminished bacterial clearance after cecal ligation and puncture with particular emphasis on the study of a subset of macrophages that have been termed 'natural suppressor' cells and have the potential to differentiate into dendritic cells.
| Murphey, E D (2012) CLP-induced impairment of innate immune function is caused by exposure to the cecal lumenal contents and not the tissue trauma or tissue ischemia/necrosis components. Microbes Infect 14:35-42 |
| Murphey, E D (2011) Cecal ligation and puncture-induced impairment of innate immune function does not occur in the absence of caspase-1. J Immunol 187:905-10 |
| Murphey, E D; Fang, Geping; Sherwood, Edward R (2008) Pretreatment with the Gram-positive bacterial cell wall molecule peptidoglycan improves bacterial clearance and decreases inflammation and mortality in mice challenged with Staphylococcus aureus. Crit Care Med 36:3067-73 |
| Murphey, E D; Sherwood, E R (2008) Pretreatment with the Gram-positive bacterial cell wall molecule peptidoglycan improves bacterial clearance and decreases inflammation and mortality in mice challenged with Pseudomonas aeruginosa. Microbes Infect 10:1244-50 |
