Sepsis, a systemic inflammatory response to infection(l), is a major cause of death within the US. (1, 2) Therapy for sepsis is mainly supportive and frequently requires admission into intensive care units,(3) with a significant financial burden to the public health system.(4) Among the multiple etiologic factors triggering sepsis, infections by Gram (-) bacteria, rank as one of the most frequent. Lipopolysaccharide (LPS) is a key component of the cell wall of Gram (-) bacteria and a potent inducers of the inflammatory response (3). In fact, an overwhelming inflammatory response is responsible for the transition between sepsis and septic shock and subsequently multiple organ failure, which are responsible for the majority casualties from sepsis. The interaction of LPS with cells of the immune system, in particular macrophages (Mo), is via a complex between CDI4 and Toll-like receptor 4 (TLR4). In this complex, CD14 is the major binding site for LPS whereas TLR4 is involved in the signal transduction responsible for the inflammatory response. Recent findings from Dr. De Maio laboratory that have implicated the role of heat shock proteins (hsps) in the trafficking of CD14.(5) Treatment of a murine M0 line (J774 Cells) with Geldanamycin (GA), a specific inhibitor of Heat Shock protein - 90 (Hsp90) family, leads to increased internalization of the membrane bound form of CD14 (mCD14). Thus, Mos treated with GA show an impaired response to LPS.(5) In addition, GA is a potent inducer of the heat shock response.(6) Thus, the effect of GA on CD14 internalization could be due to inhibition of Hsp90 function or heat shock protein expression. These two hypotheses will be addressed in this project. Furthermore, CDM was observed to accumulate within the endoplasmic reticulum (ER) after GA treatment. Since Grp94 is the ER member of the Hsp90 family, its inhibition by GA may be responsible for CD14 ER accumulation, which could be due to the unfolding of this glycoprotein within the ER. in summary, this proposal aims to characterize the biosynthesis, ER retention, and trafficking of CDM after GA treatment. These studies may elucidate the role of hsps in these cellular processes.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Predoctoral Individual National Research Service Award (F31)
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Special Emphasis Panel (ZRG1-SBIB-V (29))
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Hagan, Ann A
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University of California San Diego
Schools of Medicine
La Jolla
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Vazquez, Daniel E; Niño, Diego F; De Maio, Antonio et al. (2015) Sustained expression of lipocalin-2 during polymicrobial sepsis. Innate Immun 21:477-89
Niño, Diego F; Cauvi, David M; De Maio, Antonio (2014) Itraconazole, a commonly used antifungal, inhibits Fc? receptor-mediated phagocytosis: alteration of Fc? receptor glycosylation and gene expression. Shock 42:52-9
Drummond, Robert; Cauvi, David M; Hawisher, Dennis et al. (2013) Deletion of scavenger receptor A gene in mice resulted in protection from septic shock and modulation of TLR4 signaling in isolated peritoneal macrophages. Innate Immun 19:30-41
Drummond, Robert; Song, Donghuan; Hawisher, Dennis et al. (2012) Acute acalculous cholecystitis-like phenotype in scavenger receptor A knock-out mice. J Surg Res 174:344-51