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主要临床问题，经常导致截肢。最近包括我们的研究表明，作为成熟内皮细胞前体的内皮前体细胞在创面修复过程中对局部血管生成起关键作用，为糖尿病创面基于内皮祖细胞的细胞治疗提供了理论依据。然而，在1型和2型糖尿病患者中，内皮祖细胞血管生成功能都严重受损，直接限制了他们在临床上进行自体细胞治疗的潜力。MicroRNAs是一类新的内源性非编码小RNA，可能发挥其作为关键转录后调节因子的治疗潜力。在所有的miRNAs中，到目前为止，只有不到10个miRNAs被报道在成熟的内皮细胞中发挥促进或抑制血管生成的作用。值得注意的是，很少有信息 存在miRNA对EPC介导的血管生成的调控，特别是在疾病条件下。这个竞争性的更新建议集中在促血管生成的microrna mir-27b上，因为我们的初步研究表明，它在糖尿病内皮祖细胞中缺乏，而它的修复拯救了ePC。 起到促进糖尿病伤口愈合的作用。这一令人着迷的现象背后的机制尚不清楚。我们推测mir-27b直接抑制新的促氧化剂SHCA蛋白p66shc和/或强大的抗血管生成蛋白血栓反应蛋白-2(TSP-2)，增加锰超氧化物歧化酶(MnSOD)，降低线粒体氧化应激，从而改善EPC血管生成功能，促进2型糖尿病伤口愈合。这一假说是在对发表在 在上一次供资期间，我们的实验室在实地和一些关键的初步数据的生成方面取得了进展。我们计划检验我们的中心假设，并通过追求三个具体目标来实现我们的目标。在目标1中，我们将确定mir-27b如何改善糖尿病患者的EPC血管生成功能。在目标2中，我们将确定mir-27b在糖尿病内皮祖细胞中的直接靶点。在目标3中，我们将研究mir-27b靶向EPC细胞治疗对糖尿病患者伤口愈合的功能影响。这项研究的主要意义在于，它将首次揭示miRNAs如何调控糖尿病患者的EPC血管生成和伤口修复。确定促血管生成的mir-27b是如何调节糖尿病内皮祖细胞功能的，可能会通过miRNA修饰为越来越多患有这种毁灭性并发症的糖尿病患者的难治性伤口带来改进的自体内皮祖细胞治疗。