The role of miR-27b and PPARgamma expression during sepsis

• Applicant: Professor Dr. Andreas von Knethen
• Subject Area: Public Health, Healthcare Research, Social and Occupational Medicine
• Term: from 2008 to 2015
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 62604498

Despite intensive research, sepsis remains one major cause of death in intensive care units. Sepsis originates from an initial hyper-inflammatory phase, characterized by the uncontrolled release of proinflammatory mediators mainly by macrophages (MΦ). Diminishing this phase would limit this overwhelming response and concomitantly improve septic outcome. Inflammatory responses are often associated with decreased expression of the anti-inflammatory factor peroxisome proliferatoractivated receptorg (PPARγ), which we recently attributed to miR-27b-dependent mRNA degradation in MF in vitro. We hypothesize that PPARγ expression is reduced in sepsis and that maintaining PPARγ expression will perpetuate a confined immune response by reactivating endogenous antiinflammatory properties thus, improving sepsis outcome. Using the murine polymicrobial cecal ligation and puncture (CLP) sepsis model, we will clarify the following questions: 1) Which molecular mechanism decreases PPARγ expression in MΦ during CLP? 2) Does blockade of this signaling pathway maintain PPARγ expression in MΦ during CLP and thus, improves sepsis outcome? 3) Accordingly, will adoptive transfer of MΦ stably transduced with a PPARγ expression construct lacking regulatory 3´-sequences improve septic outcome induced by CLP?

• DFG Programme: Research Grants