下肢动脉硬化闭塞症（ASO）严重威胁中老年人健康，血管组织细胞增殖/死亡失衡导致的血管重塑是ASO进展的关键病理生理过程。我们前期研究发现ASO患者病变组织血管内皮细胞（VEC）自噬活跃。利用ASO患者临床组织标本与离体细胞模型，我们首次发现VEGFR下游接头蛋白GAB2缺失导致VEC自噬亢进，并进一步发现VEGFR-GAB2轴通过下游相关信号通路调控VEC自噬平衡，但具体机制尚未明确。由此我们提出假设：GAB2信号功能缺失是导致VEC自噬亢进，引发血管重塑的重要原因。基于前期研究基础，本项目拟在细胞和动物层面上，通过细胞生物学和分子生物学手段，揭示GAB2缺失介导的VEC自噬亢进促进血管重塑，阐明GAB2作为信号通路“集散中心”调节VEC自噬的机制，并在动物模型中通过多模态影像学手段验证调控GAB2功能维持VEC自噬平衡、进而抑制血管重塑、延缓ASO进展，为临床转化研究提供新的理论依据。

Arteriosclerosis obliterans (ASO) is a common peripheral vascular disease that seriously threatens the health of elderly people. Vascular remodeling caused by imbalance between proliferation and death of vascular tissue cells is a key pathophysiological process in the development of ASO. In our previous study, we have found that the autophagy of vascular endothelial cells (VEC) is active in the arterial tissues of ASO patients. Based on clinical tissue samples and in vitro cell models of ASO patients, we have found for the first time that the deficiency of GAB2, a downstream adaptor protein of VEGFR, results in the hyperactivity of VEC autophagy, and the VEGFR-GAB2 axis adjusts the balance of VEC autophagy through downstream related signal pathways, but the specific mechanism remains unclear. Therefore, we hypothesize that the loss of function of VEGFR-GAB2 signal axis is the main cause of VEC autophagic hyperfunction and vascular remodeling. Based on the previous research, we propose to reveal the deficiency of GAB2 mediated VEC autophagy to promote vascular remodeling at the cellular and animal level by means of cell biology and molecular biology, clarify the mechanism of GAB2 as distribution center of signal pathway adjusting VEC autophagy, verify the adjustment of GAB2 function to maintain VEC autophagy balance by multimodal imaging in animal model to inhibit vascular remodeling and delay the progress of ASO, and provide a new theoretical basis for clinical transformation research.