This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Atherosclerosis is a major vascular disease responsible for at least 40% of deaths in developed countries. Atherosclerosis risk factors include impaired lipid uptake and chronic inflammation. Chronic inflammation is caused primarily by macrophages activated by persistent infection with certain microbial pathogens to produce pro-inflammatory cytokines. Unlike most microbial pathogens, insect stages (promastigotes) of Leishmania major circumvent inflammatory responses during macrophage invasion. Determining how these responses are avoided during Leishmania invasion promises enhanced therapeutic options for treating this disease. For instance, the role of host inflammatory regulators during L. major uptake has not been fully explored. Consistent with avoidance of macrophage activation, no inflammatory toll-like receptor ligands presented by Leishmania promastigotes have yet been functionally identified.This suggests Leishmania may lack these ligands or suppress their activity. We hypothesize that Leishmania promastigotes present a repertoire of both pro and anti-inflammatory ligands but exploit anti-inflammatory host pathways to avoid macrophage activation.
Our aims are as follows:
Aim I : Establish whether L. major exploits apolipoprotein E (ApoE) in avoiding macrophage activation.
Aim II : Confirm that L. major avoidance of macrophage activation is linked to documented inhibitory host signaling pathways. In particular, we will confirm the role of TGFb in CR3 -mediated signaling cascades mediated by L. major.
Aim III : Establish whether L. major promastigotes can modulate TLR-mediated inflammatory cytokine induction. Dependent on the outcomes, we will seek to link suppressive functions of TGFb signaling to the roles of ApoE and TLR signaling, in addition to CR3 signaling, during L. major uptake.
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