Engineering NRG signaling for therapeutic vascularization in diabetic wounds

工程 NRG 信号传导用于糖尿病伤口治疗性血管化

• 批准号: 8278926
• 负责人: Steven Michael Jay
• 金额: $ 9.09万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-06-01 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8278926
• 关键词: Affinity; Amputation; 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; mortality; mouse model; new technology; novel; novel therapeutic intervention; pandemic disease; programs; receptor; research study; response; therapeutic target

DESCRIPTION (provided by applicant): 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 advances would enable new therapeutic approaches in diabetic wound healing.

描述（由申请人提供）：糖尿病是一种近流行性疾病，具有与不愈合足部溃疡（DFU）相关的大量发病率。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用于治疗DFU。然而，基于细胞的治疗性血管化尚未在大型临床试验中得到验证，常规药物和蛋白质治疗在很大程度上失败了 或者让人失望因此，开发用于治疗DFU的改进的治疗性血管化方法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受体家族与神经调节蛋白-1（NRG）的结合。虽然在癌症和许多器官系统中进行了充分的研究，但对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，并已被证明是小鼠模型中对缺血的血管生成反应的关键介质。NRG剪接变体以及NRG亚家族中的其他蛋白质也是潜在的内皮效应物，通过其对受体ErbB 3和ErbB 4的高结合亲和力。压倒性的证据表明，ErbB受体在二聚化后启动信号传导，最常见的是与另一个ErbB家族成员。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且被认为以准活化状态存在，NRG的剪接变体能够通过多个ErbB二聚体或寡聚体诱导信号传导，其中每一组可以活化独特的途径。因此，NRG/ErbB信号传导在血管形成中的作用尚不清楚，并且使ErbB配体在治疗性血管形成中的功效最大化的潜力仍未实现。在本申请中，ErbB受体在血管形成中的作用将通过追求三个特定目标来探索。目的1验证内皮细胞ErbB信号的偏性可以调节内皮细胞表型的假说。目的2中的实验将检验ErbB受体配体的局部递送可通过内皮ErbB受体介导的机制在体内刺激治疗性血管形成的假设。在目的3中，将测试皮肤替代物植入可以通过与ErbB受体配体的局部递送整合而增强的假设。在这项工作结束时，重要的 将采取步骤来阐明ErbB受体在血管形成中的作用并确定它们作为糖尿病伤口愈合中的治疗靶点的潜力。此外，该项目具有更广泛的影响;这里开发的治疗策略有可能成为组织工程领域的一项使能技术。与公共卫生的相关性-通过ErbB受体参与的治疗性血管化是一种新的，有前途的方法，可降低与非愈合性糖尿病足溃疡相关的发病率和死亡率。在这里，使用新的技术和策略，以开发一个更好的机制理解ErbB受体在血管化的建议。这一进展将为糖尿病伤口愈合提供新的治疗方法。