Dissecting pathways initiating a profibrotic and anti-angiogenic injury response in perivascular myofibroblast precursors in kidney fibrosis ((1)-P30*)

我们的数据表明，损伤驱动Gli 1+细胞脱离毛细血管，触发肾毛细血管稀疏，缺氧和肌成纤维细胞形成为纤维化的启动子。在一个公正的Gli 1细胞特异性转录组学方法中，我们确定了参与这一过程的关键途径，这些途径可能是有前途的治疗靶点。该项目将利用细胞特异性体内CRISPR/Cas9基因编辑，使用双基因Gli 1CreERt 2; Cas9小鼠诱导这些途径中的条件性功能丧失突变，最终目标是通过将Gli 1+细胞从促纤维化，抗血管生成转变为促血管生成促再生表型来阻止肾纤维化的发生。

Our data indicates that injury drives detachment of Gli1+ cells from capillaries triggering renal capillary rarefaction, hypoxia and myofibroblast formation as initiators of fibrosis. In an unbiased Gli1 cell-specific transcriptomic approach we identified critical pathways involved in this process that might be promising therapeutic targets. The project will utilize cell specific in vivo CRISPR/Cas9 gene editing to induce conditional loss of function mutations in these pathways using bigenic Gli1CreERt2; Cas9 mice with the ultimate goal to stop initiation of kidney fibrosis by switching Gli1+ cells from a pro-fibrotic, anti-angiogenic towards a pro-angiogenic pro-regenerative phenotype.