肺部疾病在我国有近5000万患者。促进肺再生对恢复病变肺的功能有重要的作用。然而病变肺如纤维化肺中的不正常重构的微环境对肺再生有抑制作用。改变病变肺微环境可抑制纤维化并促进肺再生。我们发表在 Nature (2010,2014),Cell (2011), Cancer Cell(2014), Nature Cell Biology(2015)，Nature Medicine (2016)的工作首次提出：血管内皮细胞形成“引导性微环境”调控器官再生，并防止纤维化。而血管微环境重构的节点由血小板和单核细胞调控。本项目中我们将研究肺修复中血管微环境是如何重构并促进再生，通过揭示血管内皮细胞、肺干细胞及血液细胞的相互作用阐明这一过程中的关键分子节点调控机制。我们还使用血管靶向基因编辑手段重构促再生的血管微环境。因此，本项目研究基于“血管微环境重构”在肺再生的作用和机制，具有很好的创新性和应用价值。

Lung diseases remain leading death causes. Regenerative therapy that aims to stimulate the regeneration of diseased lung tissue may provide promising treatment. Nevertheless, aberrant remodeling of pulmonary microenvironment frequently prohibits lung regeneration at pathological conditions such as lung fibrosis. Thus, elucidating how remodeling vascular microenvironment regulates lung regeneration and fibrosis has translational value. Our previous work demonstrates that endothelial cells (ECs) lining vascular lumen elaborate paracrine factors to stimulate the propagation of local facultative stem cells, functionalizing vascular niche that drives organ regeneration (Cao*..Ding* Nature Medicine 2016; Rafii..Ding* Nature Cell Biology 2015; Ding*, Cao..Nature 2014; Ding..Nature 2010; Ding..Cell 2011; Cao, Ding*..Cancer Cell 2014). This transformative notion that advances our traditional view of vascular cells as passive conduit delivering oxygen and blood. Furthermore, we also identified that key checkpoint pathways in vascular niche such as S1P1 determine the generation of pro-regenerative and anti-fibrotic factors in ECs, enabling "adaptive remodeling of vascular niche" in organ regeneration and repair. In contrast, suppression of these pathways by persistent activation of FGFR1 leads to "maladaptive remodeling of vascular niche" that instigates organ fibrosis. However, a thorough investigation of how remodeling vascular niche balances lung regeneration and fibrosis in various injury settings is lacking. As such, this application aims to define key checkpoint pathways by which remodeling vascular niche orchestrates the regeneration of damaged lungs...We will focus on revealing the central checkpoint pathways enabling the "adaptive vascular niche remodeling" that directs lung regeneration and prevents fibrosis. We will 1) delineate the molecular basis via which key checkpoint pathways determine the pro-regenerative "adaptive" versus pro-fibrotic "maladaptive" remodeling of vascular niche. Mouse EC-specific gene gain and loss of function strategy will be combined with complementary animal lung repair models to reveal the contribution of these checkpoint pathways; 2) uncover cellular players modulating the critical checkpoint pathways involved in vascular niche remodeling. Based on our previous work implicating the role of platelets in modulating vascular niche, we will examine the influence of these blood cells on vascular niche remodeling; 3) devise "interdisciplinary" approach to induce “adaptive vascular niche remodeling” that promotes regeneration and curtails fibrosis. This proposal will answer a fundamental question involved in vascular, regenerative and lung biology: how to remodel an inviting vascular niche to induce lung regeneration without fibrosis. As such, positive outcome of this study will hold therapeutic potential for vascular and lung diseases. The findings of the proposed study will also conceptually advance our understanding of how remodeling vascular niche orchestrates regeneration and repair in different organs.