Engineering NRG Signaling For Therapeutic Vascularization In Diabetic Wounds

工程 NRG 信号用于糖尿病伤口治疗性血管化

基本信息

批准号：
8639621
负责人：
Steven Michael Jay
金额：
$ 23.7万
依托单位：
UNIV OF MARYLAND, COLLEGE PARK
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-06-01 至 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8639621
关键词：
Affinity Animal Model Automobile Driving Binding Biocompatible Materials Cardiac Myocytes Cell Line Cells Chimeric Proteins Clinical Clinical Trials Data Development Diabetes Mellitus Diabetic Foot Ulcer Diabetic wound Dimerization Drug Delivery Systems Endothelial Cells Engineering Engraftment ErbB Receptor Family Protein ErbB4 gene Family member Foot Ulcer Implant Ischemia Laboratories Ligands Link Lower Extremity Malignant Neoplasms Mediating Mediator of activation protein Mentors Mitogens Modeling Molecular Molecular Biology Morbidity - disease rate Mus Neuregulin 1 Pathway interactions Pharmaceutical Preparations Phase Phenotype Property Proteins Public Health RNA Splicing Receptor Signaling Research Personnel Role Signal Transduction Skin Substitutes Technology Tertiary Protein Structure Testing Therapeutic Tissue Engineering Training Variant Vascularization Work Wound Healing angiogenesis base body system career design diabetic diabetic wound healing dimer experience improved in vivo limb amputation mortality mouse model new technology novel novel therapeutic intervention pandemic disease programs receptor research study response therapeutic target

项目摘要

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.

糖尿病是一种近乎流行的疾病，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，因此治疗性血管化方法已应用于治疗 DFU。然而，基于细胞的治疗性血管化尚未得到证实。经过大型临床试验验证，传统药物和蛋白质治疗基本上失败或已经失败令人失望。因此，开发改进的血管化治疗方法来治疗 DFU 将满足关键的临床需求。分子治疗血管化的一种新兴策略是 ErbB 受体家族与 Neuregulin-1 (NRG) 的结合。尽管对癌症和许多疾病进行了深入研究对于器官系统中 NRG/ErbB 信号传导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通过与受体 ErbB3 和 ErbB4 的高结合亲和力，成为潜在的内皮效应子。压倒有证据表明 ErbB 受体在二聚化后启动信号传导，最常见的是与另一个 ErbB 家属。鉴于有四种已知的 ErbB 受体，其中之一 (ErbB2) 没有已知的配体并被认为以准激活状态存在，NRG 的剪接变体能够诱导通过多个 ErbB 二聚体或寡聚体进行信号传导，每组都可以激活独特的途径。因此， NRG/ErbB 信号在血管形成中的作用尚不清楚，并且有可能最大限度地发挥 ErbB 的功效治疗性血管化中的配体仍未实现。在此应用中，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 ErbB 信号传导可以调节内皮细胞表型。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整合来增强。在此结论下工作，朝着阐明 ErbB 受体在血管化中的作用并确定其作用迈出了重要的一步作为糖尿病伤口愈合治疗靶点的潜力将被采用。此外，该项目还有更广泛的影响；这里开发的治疗策略有可能成为一种有利的治疗策略组织工程领域的技术。与公共卫生的相关性 - 治疗性血管化 ErbB 受体的参与是降低发病率和死亡率的一种新颖且有前景的方法与不愈合的糖尿病足溃疡有关。在这里，利用新技术和策略来开发提出了对 ErbB 受体在血管化中的改进机制的理解。这一进展将为糖尿病伤口愈合提供新的治疗方法。