Engineering NRG Signaling For Therapeutic Vascularization In Diabetic Wounds

糖尿病是一种近乎大流行的疾病，其发病率与不愈合的足部溃疡（DFU）相关。 血管生成受损是糖尿病患者伤口愈合的限制因素，因此是治疗性血管化的限制因素 已经应用了一些方法来处理DFU。然而，基于细胞的治疗性血管化还没有被发现。 在大型临床试验中得到验证，常规的药物和蛋白质治疗在很大程度上失败或被 失望因此，开发治疗DFU的改良血管化治疗方法 可以满足临床上的急需一种新兴的分子血管化治疗策略是 ErbB受体家族与神经调节蛋白-1（NRG）的接合。虽然在癌症和许多 在器官系统中，对NRG/ErbB信号在血管形成中的作用知之甚少。NRG是一个 已知的内皮细胞有丝分裂原，并已被证明是血管生成反应的关键介质， 小鼠模型中的缺血。NRG剪接变体，以及NRG亚家族中的其他蛋白质，也是 通过其对受体ErbB 3和ErbB 4的高结合亲和力而成为潜在的内皮效应物。压倒性 有证据表明ErbB受体在二聚化后启动信号传导，最常见的是与另一个ErbB 家庭成员鉴于存在四种已知的ErbB受体，其中一种（ErbB 2）不具有已知的 配体，并被认为存在于一个准活化状态，剪接变异体的NRG是能够诱导 通过多个ErbB二聚体或寡聚体进行信号传导，其中的每一组可以激活独特的途径。因此，在本发明中， NRG/ErbB信号在血管形成中的作用尚不清楚， 配体在治疗性血管形成中的应用仍未实现。在本申请中，研究了ErbB受体在 将通过追求三个具体目标来探索血管化。目标1将检验以下假设： 内皮细胞ErbB信号通路可调节内皮细胞表型。目标2中的实验将测试 假设ErbB受体配体的局部递送可以通过 内皮ErbB受体介导的机制。在目标3中，假设皮肤替代物植入可以 将测试通过与ErbB受体配体的局部递送的整合而增强。在这一结论 工作，重要的步骤，澄清ErbB受体在血管化中的作用，并确定其 作为糖尿病伤口愈合的治疗靶点的潜力将被考虑。此外，该项目还 更广泛的影响;这里开发的治疗策略有可能作为一个使 组织工程领域的技术。与公共卫生的相关性-通过 ErbB受体的参与是一种新的，有前途的方法，以减少发病率和死亡率 与不愈合的糖尿病足溃疡有关。在这里，利用新技术和战略来开发一个 提出了对ErbB受体在血管形成中的机制的改进理解。这种装置可以 为糖尿病伤口愈合提供新的治疗方法。

Diabetes is a near-pandemic disease with substantial morbidity associated with non-healing foot ulcers (DFUs). Impaired angiogenesis is a limiting factor for wound healing in diabetics, and thus therapeutic vascularization approaches have been applied to treat DFUs. However, cell-based therapeutic vascularization has yet to be validated in large clinical trials and conventional drug and protein treatments have largely failed or been disappointing. Therefore, the development of improved therapeutic vascularization approaches to treat DFUs would fill a critical clinical need. One emerging strategy for molecular therapeutic vascularization is engagement of the ErbB receptor family with Neuregulin-1 (NRG). Though well studied in cancer and many organ systems, relatively little is known about the role of NRG/ErbB signaling in vascularization. NRG is a known endothelial cell mitogen and has been shown to be a crucial mediator of the angiogenic response to ischemia in a mouse model. NRG splice variants, as well as other proteins in the NRG subfamily, are also potential endothelial effectors via their high binding affinity to receptors ErbB3 and ErbB4. Overwhelming evidence indicates that ErbB receptors initiate signaling following dimerization, most often with another ErbB family member. Given that there are four known ErbB receptors, one of which (ErbB2) does not have a known ligand and is thought to exist in a quasi-activated state, splice variants of NRG are capable of inducing signaling through multiple ErbB dimers or oligomers, each set of which may activate a unique pathway. Thus, the role of NRG/ErbB signaling in vascularization is unclear and the potential to maximize the efficacy of ErbB ligands in therapeutic vascularization remains unrealized. In this application, the role of ErbB receptors in vascularization will be explored by pursuing three specific aims. Aim 1 will test the hypothesis that biasing of endothelial ErbB signaling can regulate endothelial cell phenotype. Experiments in Aim 2 will test the hypothesis that local delivery of ErbB receptor ligands can stimulate therapeutic vascularization in vivo via an endothelial ErbB receptor-mediated mechanism. In Aim 3, the hypothesis that skin substitute engraftment can be enhanced via integration with local delivery of ErbB receptor ligands will be tested. At the conclusion of this work, significant steps towards clarifying the role of ErbB receptors in vascularization and determining their potential as therapeutic targets in diabetic wound healing will have been taken. Furthermore, this project has broader implications; the therapeutic strategies developed here have the potential to serve as an enabling technology in the field of tissue engineering. Relevance to Public Health - Therapeutic vascularization via engagement of ErbB receptors is a novel, promising approach to decreasing morbidity and mortality associated with non-healing diabetic foot ulcers. Here, the use of new technology and strategies to develop an improved mechanistic understanding of ErbB receptors in vascularization is proposed. This advance would enable new therapeutic approaches in diabetic wound healing.