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

尽管有深入的研究，败血症仍然是重症监护病房死亡的主要原因之一。脓毒症起源于最初的高炎症期，其特征是主要由巨噬细胞不受控制地释放促炎介质（MΦ）。减少这一阶段将限制这种压倒性的反应，并同时改善败血症的结果。炎症反应通常与抗炎因子过氧化物酶体增殖激活受体（PPARγ）的表达降低有关，我们最近将其归因于体外MF中mir -27b依赖性mRNA降解。我们假设PPARγ表达在脓毒症中降低，维持PPARγ表达将通过重新激活内源性抗炎特性来延续有限的免疫反应，从而改善脓毒症的预后。利用小鼠多微生物盲肠结扎和穿刺（CLP）脓毒症模型，我们将澄清以下问题：1)CLP期间，哪种分子机制降低MΦ中PPARγ的表达？2)阻断该信号通路是否能维持CLP期间MΦ中PPARγ的表达，从而改善脓毒症的预后？3)因此，通过缺乏调节3´序列的PPARγ表达构建体稳定转导MΦ的过继性转移是否会改善CLP诱导的败血症结局？

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?