Analysis of Tgsl, a novel regulator of macrophage survival

描述（由申请人提供）：巨噬细胞具有广泛的功能，从防御病原体到清除代谢的有毒产物。因此巨噬细胞参与了大量感染性、炎症性和代谢性疾病的发病机制。LXR核激素受体通路在巨噬细胞活力调控中起关键作用。LXR配体是氧化脂质，LXR信号控制参与脂质代谢的蛋白质表达。此外，LXR还控制炎症相关分子的表达，包括巨噬细胞生存因子CD5L。我们发现TGS1是CD5L的一种新的调节因子，它被3' UTR顺式调节元件紧密抑制。值得注意的是，我们的数据显示，对TGS1产生的抑制在LPS的作用下得到缓解，导致CD5L的下调。LPS似乎通过诱导对an的利用来发挥其作用

DESCRIPTION (provided by applicant): Macrophages perform a wide range of functions, from defense against pathogens to removal of toxic products of metabolism. As such macrophages are involved in pathogenesis of a large number of infectious, inflammatory and metabolic diseases. The LXR nuclear hormone receptor pathway plays a key role in regulation of macrophage viability. LXR ligands are oxidized lipids and LXR signaling controls the expression of proteins involved in lipid metabolism. In addition LXR controls the expression of molecules involved in inflammation, including CD5L, a macrophage survival factor. We identified TGS1 as a novel regulator of CD5L that is tightly repressed by 3' UTR cis regulatory elements. Significantly, our data show that repression of TGS1 production is relieved in response to LPS, resulting in down-regulation of CD5L. LPS appears to exert its effect by inducing utilization of an upstream alternative Tgs1 polyadenylation site. Our discoveries provide a strong support for TGS1 as a molecule that connects inflammatory and metabolic signaling. We propose to carry out a set of experiments that will 1. Determine the mechanism of post-transcriptional control of Tgs12. Identify regulators of TGS1 post-transcriptional control machinery. By pursuing the proposed aims we will identify trans effectors that act on TGS1 3'UTR cis control elements and characterize TGS1 targets. Moreover we will confirm the role of inducible alternative polyadenylation in regulation of the LXR pathway that controls viability of macrophages. Results of our study will reveal novel details of cross-regulation of metabolic and inflammatory pathways and will therefore have a broad impact on our understanding of pathogenesis of a wide range of diseases