MicroRNA Regulation of Endothelial Progenitor Cell Function and Wound Healing

MicroRNA 对内皮祖细胞功能和伤口愈合的调节

• 批准号: 8974189
• 负责人: Alex F Chen
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-03-01 至 2017-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8974189
• 关键词: Adaptor Signaling Protein; Affect; Amputation; Angiogenesis Inhibitors; Angiogenic Proteins; Attenuated; Autologous; Base Pairing; Binding; Blood flow; Cell Therapy; Cell physiology; Clinical; Clinical Protocols; Complication; Data; Diabetes Mellitus; Diabetic mouse; Diabetic wound; Disease; Endothelial Cells; Foot Ulcer; Funding; Gene Expression; Generations; Healed; Hyperglycemia; Knowledge; Laboratories; Lead; Manganese Superoxide Dismutase; Mediating; MicroRNAs; Mitochondria; Modification; Non-Insulin-Dependent Diabetes Mellitus; Outcome Study; Oxidative Stress; Patients; Play; Proteins; Publishing; Reactive Oxygen Species; Refractory; Regulation; Regulator Genes; Reporting; Role; Stem cells; Testing; Therapeutic; Time; Translating; Translations; Untranslated RNA; Work; Wound Healing; angiogenesis; base; diabetic; diabetic patient; diabetic wound healing; fascinate; healing; improved; in vivo; mouse ShcA protein; novel; novel strategies; p66(ShcA) protein; pre-clinical; repaired; response; restoration; success; thrombospondin 2; wound

DESCRIPTION (provided by applicant): Refractory wound is a major clinical problem in diabetic patients that often leads to amputations. Recent studies including ours suggest that endothelial progenitor cells (EPCs), precursor of mature endothelial cells, critically contribute to local angiogenesis in wound repair, providing th proof of concept of EPC-based cell therapy for diabetic wounds. However, EPC angiogenic functions are severely impaired in both type 1 and type 2 diabetic patients, directly limiting thei potential for autologous cell therapies clinically. MicroRNAs are a new class of small endogenous non-coding RNAs that may exert their therapeutic potential as key post-transcriptional regulators. Among all miRNAs, less than 10 of them have been reported to exert pro- or anti-angiogenic effects in mature endothelial cells to date. Remarkably, little information exist on miRNA regulation of EPC-mediated angiogenesis, especially under disease conditions. This competitive renewal proposal focuses on pro-angiogenic microRNA mir-27b because our preliminary studies indicate that it is deficient in diabetic EPCs, and its restoration rescues EPC functions and accelerates diabetic wound healing. The mechanisms underlying this fascinating phenomenon remain unclear. We hypothesize that mir-27b directly suppresses a novel pro-oxidant ShcA protein p66shc and/or potent anti-angiogenic protein thrombospondin-2 (TSP-2), with increased manganese superoxide dismutase (MnSOD) and reduced mitochondrial oxidative stress that result in improved EPC angiogenic function and accelerated wound healing in type 2 diabetes. This hypothesis is formulated after a careful analysis of published work in the field and the generation of some key preliminary data in our laboratory during the last funding period. We plan to test our central hypothesis and accomplish our objective by pursuing three specific aims. In Aim 1, we will determine how mir-27b improves EPC angiogenic function in diabetes. In Aim 2, we will determine the direct target of mir-27b in diabetic EPCs. In Aim 3, we will examine the functional consequences of mir-27b targeted EPC cell therapy on wound healing in diabetes. The major significance of this study is that it will delineate for the first tme how miRNAs regulate EPC angiogenesis and wound repair in diabetes. Determine how diabetic EPC functions are regulated by pro-angiogenic mir-27b could lead to improved autologous EPC cell therapy with miRNA modification for refractory wounds in increasing number of diabetic patients who suffer from this devastating complication.

描述（由申请人提供）： 难治性伤口是糖尿病患者的一个主要临床问题，常常导致截肢。包括我们在内的最近研究表明，内皮祖细胞 (EPC)（成熟内皮细胞的前体）对伤口修复中的局部血管生成至关重要，这为基于 EPC 的糖尿病伤口细胞疗法提供了概念证明。然而，1型和2型糖尿病患者的EPC血管生成功能均严重受损，直接限制了自体细胞疗法的临床潜力。 MicroRNA 是一类新型的小型内源性非编码 RNA，可以发挥其作为关键转录后调节因子的治疗潜力。迄今为止，在所有 miRNA 中，据报道只有不到 10 个 miRNA 在成熟内皮细胞中发挥促血管生成或抗血管生成作用。值得注意的是，信息很少 存在于 EPC 介导的血管生成的 miRNA 调节中，尤其是在疾病条件下。这项竞争性更新提案重点关注促血管生成的 microRNA mir-27b，因为我们的初步研究表明它在糖尿病 EPC 中存在缺陷，而其修复可挽救 EPC 发挥作用并加速糖尿病伤口愈合。这一令人着迷的现象背后的机制仍不清楚。我们假设 mir-27b 直接抑制新型促氧化剂 ShcA 蛋白 p66shc 和/或强效抗血管生成蛋白血小板反应蛋白-2 (TSP-2)，同时增加锰超氧化物歧化酶 (MnSOD) 并减少线粒体氧化应激，从而改善EPC 血管生成功能和加速 2 型糖尿病伤口愈合。这一假设是在对已发表的论文进行仔细分析后提出的。 领域以及我们实验室在上一次资助期间生成的一些关键初步数据。我们计划通过追求三个具体目标来检验我们的中心假设并实现我们的目标。在目标 1 中，我们将确定 mir-27b 如何改善糖尿病中的 EPC 血管生成功能。在目标 2 中，我们将确定 mir-27b 在糖尿病 EPC 中的直接靶标。在目标 3 中，我们将研究 mir-27b 靶向 EPC 细胞疗法对糖尿病伤口愈合的功能影响。这项研究的主要意义在于，它将首次阐明 miRNA 如何调节糖尿病中 EPC 血管生成和伤口修复。确定促血管生成 mir-27b 如何调节糖尿病 EPC 功能，可能会改善自体 EPC 细胞疗法，并通过 miRNA 修饰来治疗越来越多患有这种破坏性并发症的糖尿病患者的难治性伤口。