权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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：
8475652
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
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-06-01 至 2013-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8475652
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

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）：糖尿病是一种近乎流行的疾病，其发病率与未愈合足部溃疡（DFUs）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被应用于治疗DFUs。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，传统的药物和蛋白质治疗在很大程度上失败了

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Oncogene Knockdown via Active Loading of Small RNAs into Extracellular Vesicles by Sonication.

DOI：
10.1007/s12195-016-0457-4
发表时间：
2016-09
期刊：
CELLULAR AND MOLECULAR BIOENGINEERING
影响因子：
2.8
作者：
Lamichhane, Tek N.;Jeyaram, Anjana;Patel, Divya B.;Parajuli, Babita;Livingston, Natalie K.;Arumugasaamy, Navein;Schardt, John S.;Jay, Steven M.
通讯作者：
Jay, Steven M.

Impact of cell culture parameters on production and vascularization bioactivity of mesenchymal stem cell-derived extracellular vesicles.