Engineering NRG Signaling For Therapeutic Vascularization In Diabetic Wounds

糖尿病是一种几乎是大流行的疾病，与无法愈合的足部溃疡(DFU)相关的发病率很高。 血管生成受损是糖尿病患者伤口愈合和治疗血管形成的限制因素。 治疗DFU的方法已被应用。然而，以细胞为基础的治疗性血管形成尚未得到 在大型临床试验和常规药物和蛋白质治疗中得到验证的大部分都是失败的或 令人失望。因此，改良的治疗性血管化术治疗DFU的发展 就能满足临床上的迫切需要。分子治疗性血管化的一种新兴策略是 ErbB受体家族与神经调节蛋白-1(NRG)的结合。虽然在癌症和许多方面都很有研究 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是一种 已知的内皮细胞有丝分裂原，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剪接变异体以及NRG亚家族中的其他蛋白质也是 通过与ErbB3和ErbB4受体的高结合亲和力而产生潜在的内皮效应。压倒性的 证据表明，ErbB受体在二聚化后启动信号传递，最常见的是与另一个ErbB 家庭成员。假设有四个已知的ErbB受体，其中一个(ErbB2)没有已知的 配体，并被认为存在于准激活状态，NRG的剪接变体能够诱导 通过多个ErbB二聚体或寡聚体发出信号，其中每一组都可能激活一条独特的途径。因此， NRG/ErbB信号在血管形成中的作用尚不清楚，也不清楚是否有可能最大化ErbB的疗效 配体在治疗性血管形成中的作用仍未实现。在这一应用中，ErbB受体在 血管化将通过追求三个具体目标来探索。目标1将检验以下假设 内皮细胞ErbB信号对内皮细胞表型有调节作用。Aim 2中的实验将测试 局部递送ErbB受体配体可通过血管生成促进体内治疗性血管形成的假说 内皮细胞ErbB受体介导的机制。在目标3中，皮肤替代物植入可以 将测试通过与ErbB受体配体的本地传递整合而增强的能力。在此结束时 工作，在阐明ErbB受体在血管形成中的作用并确定其 作为糖尿病伤口愈合的潜在治疗靶点将被采用。此外，这个项目已经 更广泛的影响；这里制定的治疗策略有可能成为一种 组织工程领域的技术。与公共卫生的相关性-治疗性血管化术通过 ErbB受体的参与是降低发病率和死亡率的一种新的、有希望的方法 与无法愈合的糖尿病足部溃疡有关。在这里，使用新技术和战略来开发 改进了对ErbB受体在血管形成中的机制的理解。这一进展将 在糖尿病伤口愈合方面启用新的治疗方法。

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.