YAP/TAZ响应瘢痕刚度介导“促生存”信号通路在尿道狭窄肌成纤维细胞凋亡逃避中的作用机制及靶向干预研究

顽固的纤维瘢痕形成是影响尿道狭窄治疗效果的一个重要因素。瘢痕形成均伴随着细胞外基质（ECM）刚度的改变。研究发现增加ECM刚度可引起介导力学信号转导的重要协调分子YAP/TAZ在肌成纤维细胞（瘢痕形成的关键效应细胞）核内聚集并激活，引起下游分子级联反应，促生存蛋白BCL-XL/BCL-2抑制线粒体凋亡通路降低细胞对凋亡的敏感性，发挥促肌成纤维细胞生存的生物学效应，最终形成持续稳定的瘢痕。该信号通路的作用分子机制在不同组织中具有差异，目前缺乏相关分子通路在尿道瘢痕组织中的研究。本项目拟从力学信号转导和分子生物学信号串联线索深入探讨ECM刚度介导的“促生存”信号通路在顽固尿道狭窄瘢痕形成中的作用机制，尝试筛选有效治疗靶点。以此为基础，结合同轴“壳-芯”结构（胶原酶I–靶点药物/聚乳酸/聚己内酯）的纳米纤维缓释支架，新西兰兔尿道狭窄模型初步评价该靶向干预在尿道狭窄中的治疗效应。

Fibrous scar pattern is a critical factor affecting the treatment of urethral strictures. Scar development is accompanied by changes in the stiffness of the extracellular matrix (ECM). Studies have identified that increasing the stiffness of ECM can lead YAP/TAZ, an important coordinating molecule that mediates mechanotransduction, to accumulate in the nucleus of myofibroblasts (the key effector cells for scar formation) and is activated to translate the mechanical signal, resulting in downstream molecular cascades and then weakening the sensitivity of cell apoptosis through the mitochondrial apoptosis pathway by the pro-survival proteins BCL-XL/BCL-2. It finally promotes the survival of myofibroblasts and causes the formation and persistence of rigid scars. The molecular mechanism of this signaling pathway is different in different tissues. At present, the mechanism of biological effects mediated by ECM stiffness in scars of urethral stricture is lacking. We intend to explore the mechanism of the ECM stiffness-mediated “pro-survival” signal pathway in the formation of persistent urethral stricture scars through mechanical signal transduction and molecular biological signal cues and then trying to screen the curative therapeutic target according to the mechanism. Basing on findings of the mechanism, the coaxial “shell-core” structure (Collagenase I-target drug/polylactic acid/polycaprolactone) nano-fiber drug sustained-release stent will be prepared, and the New Zealand rabbit model of urethral stricture is used to evaluate the therapeutic effect of this targeted intervention in urethral stricture.