This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Atherosclerosis is both a lipid deposit disease and a chronic inflammation process. A vicious cycle between cholesterol accumulation and inflammatory response exists in macrophages and directly presents the partnership of cholesterol and inflammation in atherosclerosis. Oxidized LDL (oxLDL) and Toll-like receptor 4 (TLR4) on macrophages trigger an inflammatory signaling in which many details are unclear. MicroRNAs (miRs) are short non-coding RNA molecules capable of regulating gene expression post-transcriptionally through base pairing with mRNAs, resulting in either translational repression or mRNA degradation. They are estimated to regulate up to a third of all human genes and play critical roles in multiple biological processes, including cell differentiation, cancer transformation and immunity development, thus emerging as new targets for the diagnosis and therapy of human diseases. One miR, miR155 has been demonstrated to be oncogenic and to play a crucial role in immune response regulation. Recent studies have revealed that miR155 expression in macrophages is up-regulated upon stimulation with multiple ligands for TLRs. While TLRs and their ligands are fundamentally involved in atherogenesis, the relationship between macrophage miR155 and atherosclerosis has not been investigated. Our preliminary studies suggest that: 1) miR155 is up-regulated in mouse peritoneal macrophages by oxidized low density lipoprotein (oxLDL) and lipopolysaccharide (LPS) in a TLR4-dependent manner;macrophage miR155 expression positively correlates with the expression of pro-inflammatory cytokines under various conditions;2) Lentivirus-mediated overexpression of miR155 enhances macrophage inflammatory response to oxLDL and LPS, and impairs macrophage cholesterol efflux;3) MiR155 expression is increased in mouse atherosclerotic lesions. In order to further investigate the role of macrophage miR155 in atherogenesis and develop strategies to halt atherosclerosis through manipulating macrophage miR155 expression, we propose to test our central hypothesis that macrophage miR155 promotes atherosclerosis through modulating macrophage function. We propose three objectives: 1. To test the hypothesis that miR155 is up-regulated in atherosclerotic lesion macrophages;2. To investigate the molecular mechanism of miR155 function in macrophages;3. To test the hypothesis in an in vitro 3D model that miR155 promotes macrophages foam cell formation and inflammation.
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