调控血管微环境代谢通路从而促进纤维化肺的再生

Lung regeneration is frequently prohibited by injury. Reprogramming the microenvironmental cues might stimulate regeneration over fibrosis in the lungs. We have shown demonstrated that vascular endothelial cells (ECs) form a niche to regulate the regeneration and fibrosis in the injured lung. Ectopic expression of paracrine factor in the pulmonary capillary endothelial cell (PCEC) enhances the regenerative integration of human alveolar type 2 cells (AEC2s) in mouse lungs. Compared to extopic expression of paracrine factor, reprogramming of metabolic pathways in the vascular niche might enable a wider range of pro-regenerative signaling. Thus, we hypothesize that reprogramming of key metabolic pathways in the endothelial (vascular) niche choreographs lung regeneration over fibrosis...We will investigate how metabolic signaling establishes a pro-regenerative and anti-fibrotic lung endothelial niche. Then we will test whether combinatorial reprogramming of metabolic pathway in the injured vascular niche will reinstate regeneration in the fibrotic lungs. We shall also test if combination of gene delivery and agonist activation in the vascular niche enhances integration of human lung progenitor cells in immunodeficient mice. ..Performing the proposed studies will help to identify potential “druggable” metabolic targets in the vascular niche to enhance lung regeneration and prevent fibrosis. This study may enable transformative “vascular niche-targeted” regenerative therapy to treat devastating lung diseases.

肺部疾病在我国有近亿患者。促进肺再生有望推动肺病治疗。我们的以往一系列工作发现血管可形成微环境(Vascular Niche)调控肺的再生能力。本申请将研究如何通过调控血管微环境“关键代谢通路”促进肺再生并防止纤维化。我们将发掘血管微环境中调控肺再生和纤维化的未知代谢通路，并利用小分子药物和血管靶向的手段在病变肺中重构“促再生的血管微环境”从而促进人源性肺干细胞在免疫缺陷鼠中的植入，建立人源化小鼠和大动物肺血管再生模型。本研究将运用血管特异性基因敲除小鼠，血管靶向和单细胞测序技术，人源性肺干细胞体内移植和大动物肺血管修复模型等多个前沿手段，探索调控器官再生的血管微环境机理。并发掘靶向血管微环境的再生治疗手段。

本项目着重解决的关键学问题是如何通过改变由血管内皮细胞组成的微环境，尤其是血管中代谢通路，促进肺再生并防止纤维化。课题组围绕项目目标，我们研究发现，1）靶向异常内皮细胞节点分子可能有助于在多个器官的修复中促进“无疤痕再生”，有望为纤维化器官的再生治疗研发过程中的新靶点。2）表观遗传重编程的血管适应导致肝纤维化，同时指出在NASH进程中血管分泌素IGFBP7和ADAMTS1作为血管微环境治疗靶点和以及作为肝纤维化生物标记物的转化意义。3）肝脏中巨噬细胞和内皮细胞存在相互交流并调控肝脏的纤维化进程，为临床上以GPCR为靶点、设计抗肝纤维化的药物提供了理论基础。4）我们发现PARP-1通过Runx2抑制减轻糖尿病动脉粥样硬化钙化和减少小鼠血管硬化。.项目执行期间所取得相应的研究进展，以通讯作者在Cell metabolism, Science Translational Medicine, Journal of Hepatology，Cell Research等杂志发表文章11篇。