TSP1-CD47 Signaling Limits Restoration of Decellularized and Synthetic Tracheal Transplants

 描述（由申请人提供）：气管损伤和缺陷虽然不常见，但在许多情况下是致命的或致残的发病率的来源。尽管制定了修复方案，如滑动气管成形术，但仍有一部分患者无法获得治疗。这些包括先天性气管发育不全（有或无食管瘘）的儿科患者和气管肿瘤的成人患者。在这些患者中，气管移植或生物工程移植物替代将是一种挽救生命的治疗方法。分泌的基质细胞蛋白血小板反应蛋白-1（TSP 1）在细胞应激下沉积在细胞外基质中。它与其高亲和力细胞受体CD 47结合。TSP 1激活CD 7通过影响血管生成和自我更新冗余地抑制组织存活。因此，（1）保留在细胞外基质中，或（2）由迁移到这种移植物中并重新增殖的细胞分泌的TSP 1可能限制移植物和整个移植物的存活。我假设 TSP 1通过细胞表面受体CD 47抑制脱细胞气管移植物内的细胞存活、植入和血管再生。我的目标是测试以下三个子假设：（1）诱导TSP 1-CD 47信号传导以抑制脱细胞和合成气管移植物的细胞恢复，（2）TSP 1通过CD 47抑制自我更新途径以限制损伤后气道上皮和气道血管生成的恢复，和（3）干扰TSP 1-CD 47信号传导轴（通过使用突变小鼠模型或治疗性阻断）可以改善原位气管移植的结果。这些目标的成功完成将提供一个新的机制，细胞-基质相互作用限制细胞的生存和重建的脱细胞和合成气管移植物的洞察力。这个建议产生的知识将支持使用CD 47阻断治疗，以改善组织工程移植的结果。

 DESCRIPTION (provided by applicant): Tracheal injuries and defects though uncommon are in many instances fatal or a source of crippling morbidity. Despite the development of reparative protocols such as slide tracheoplasty, there remains a population of patients for which there are no therapies available. These include pediatric patients with congenital tracheal agenesis (with or without an esophageal fistula), and adults with tracheal tumors. In these patients, tracheal transplantation or replacement with a bioengineered graft would be a life-saving therapy. The secreted matrix-cellular protein thrombospondin-1 (TSP1) is deposited in the extracellular matrix by cells under stress. It ligates with its high affinity cell receptor, CD47. TSP1 activation of CD7 redundantly inhibits tissue survival through effects on angiogenesis and self-renewal. Thus, TSP1 which is (1) retained in the extracellular matrix, or (2) is secreted by cells migrating into and repopulating such grafts, can limit the survival of grafts and whole transplants. I hypothesize that TSP1, via cell-surface receptor CD47, inhibits cellular survival, engraftment, and revascularization within decellularized tracheal grafts. I aim to test the following three sub-hypothesis: (1) that TSP1-CD47 signaling is induced to inhibit cellular restoration of decellularized and synthetic tracheal transplants, (2) that TSP1, via CD47, inhibits self-renewal pathways to limit recovery of the airway epithelium and airway angiogenesis after injury, and (3) that interference with the TSP1-CD47 signaling axis (via the use of mutant mouse models or therapeutic blockade) can improve outcomes in orthotopic tracheal transplantation. Successful completion of these aims will provide insight into a novel mechanism by which cell-matrix interactions limit cell survival and reconstitution of decellularized and synthetic tracheal grafts The knowledge generated by this proposal will support the use of CD47-blocking therapeutics to improve outcomes in tissue engineered transplants.