Tissue Oxygenation and Wound Healing

组织氧合和伤口愈合

• 批准号: 8838821
• 负责人: Chandan K Sen
• 金额: $ 30.03万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8838821
• 关键词: ACVR1B gene; ARNT gene; Address; Adult; Affect; Cell Hypoxia; Cell Respiration; Cells; Chronic; Clinical; Clinical Research; Code; Collagen; Disease; Endothelial Cells; Enrollment; Epidermis; Etiology; Future; Gene Targeting; Genes; Growth; Healed; Health; Human; Hypoxia; Immigration; Infection; Ischemia; Leg Ulcer; Letters; Longitudinal Studies; Metabolism; MicroRNAs; Mitochondria; Molecular; Mus; Nitric Oxide; Nobel Prize; Ohio; Outcome; Oxidation-Reduction; Oxygen; Pathway interactions; Patients; Peripheral; Reactive Oxygen Species; Research Infrastructure; Resources; Signal Transduction; Skin; Societies; System; Testing; TimeLine; Tissues; Translational Research; United States; Universities; Untranslated RNA; Up-Regulation; Vascular Diseases; Vascular blood supply; Visit; Wound Healing; clinical care; fighting; healing; human tissue; hypoxia inducible factor 1; in vivo; keratinocyte; migration; non-diabetic; novel; prospective; research study; response; tissue oxygenation; transcription factor; validation studies; wound

DESCRIPTION (provided by applicant): ABSTRACT Oxygenation state of the wound tissue is known to influence wound outcomes by a number of mechanisms ranging from enabling oxidative metabolism, fighting infection, hydroxylating collagen, generating nitric oxide, and generating reactive oxygen species which may support redox signaling. The etiology of chronic ischemic wounds is generally multi-factorial of which hypoxia caused by underlying peripheral vasculopathy is a common factor. Hypoxia is generally viewed as being angiogenic. So why does the ischemic wound not close even faster? Although hypoxia may have favorable effects on endothelial cells, the hypoxia-inducible transcription factor HIF specifically induces growth arrest of keratinocytes compromising wound closure. HIF1¿ is abundant in basal keratinocytes at the wound edge and causes growth arrest. Our observation directly implicates hypoxia-inducible microRNA (miRNA) or hypoxamir in arresting keratinocyte function. Specifically, we noted that the hypoxamir miR-210 silences target genes which would arrest growth/migration as well as repress mitochondrial metabolism in keratinocytes. In both mice and chronic wound patients, ischemic wounds showed elevated miR-210 levels. Next, we screened for miR-210 dependent pathways that would impair wound re-epithelialization. We studied the candidate pathways that emerged from murine studies for their relevance to human chronic wounds. Those specific pathways that emerged from murine studies and were successfully validated using human chronic wound-edge tissue were selected for study in this proposal. microRNA (miR or miRNA) represents a class of recently discovered non-coding (nc) genes that are of such extraordinary significance in human health and disease. Whether a set of coding gene would be functional or silenced is decided by specific miRs targeting that set of genes. As we seek to take the study of tissue oxygenation and wound healing to the future, we have chosen to focus on unveiling the significance of hypoxamir miR-210 in regulating wound closure. Three aims are proposed: Aim 1: Characterize mechanisms underlying miR-210 dependent compromised wound re-epithelialization of ischemic wounds. ¿1.1 Ischemic wound-associated elevation of miR-210 silences ISCU1/2 inhibiting mitochondrial metabolism; ¿1.2 Elevated miR-210 silences E2F3 causing p53 activation and inhibition of keratinocyte proliferation; ¿1.3 miR-210 up-regulation silences ACVR1B impeding keratinocyte migration. Aim 2: Determine molecular mechanisms underlying induction of miR-210 by ischemia; Central hypothesis: Wound ischemia induces keratinocyte miR-210 via HIF1¿ and lactate. ¿2.1 HIF-1¿/ARNT and novel co- activators drive hypoxia-induced miR-210 expression; ¿2.2 Lactate drives miR-210 expression. Aim 3: Elevated miR-210 in the epidermis of ischemic human wound edge tissue is associated with poor healing outcome in a setting of standard clinical care. We propose a prospective longitudinal study where adult non-diabetic patients with chronic leg ulcers visiting the OSU Comprehensive Wound Center will be enrolled.

描述(申请人提供)：已知伤口组织的氧合状态通过多种机制影响伤口结局，包括促进氧化代谢、抗感染、羟化胶原、产生一氧化氮和产生支持氧化还原信号的活性氧。慢性缺血性创面的病因一般是多因素的，其中由周围血管病变引起的缺氧是常见的因素。缺氧通常被认为是血管生成的。那么，为什么缺血伤口不能更快地闭合呢？虽然低氧可能对内皮细胞有有利的影响，但低氧诱导的转录因子HIF特异性地诱导损害伤口闭合的角质形成细胞的生长停止。HIF1在伤口边缘的基底层角质形成细胞中大量存在，并导致生长停滞。我们的观察直接涉及低氧诱导的microRNA(MiRNA)或低氧抑制角质形成细胞的功能。具体地说，我们注意到，低氧核糖核酸miR-210沉默了角质形成细胞中阻止生长/迁移以及抑制线粒体新陈代谢的靶基因。在小鼠和慢性创面患者中，缺血创面显示miR-210水平升高。接下来，我们筛选了会损害伤口再上皮化的miR-210依赖通路。我们研究了从小鼠研究中出现的候选通路，以确定它们与人类慢性伤口的相关性。这些从小鼠研究中出现并使用人类慢性伤口边缘组织成功验证的特定途径被选为本方案中的研究对象。MicroRNA(miR或miRNA)是最近发现的一类在人类健康和疾病中具有非常重要意义的非编码(NC)基因。一组编码基因是有功能的还是沉默的，取决于针对这组基因的特定MIR。随着我们寻求将组织氧合和伤口愈合的研究带到未来，我们选择了重点揭示subxamir miR-210在调节伤口闭合方面的意义。提出了三个目标：目标1：研究依赖miR-210的受损创面再上皮化的机制。1.1缺血损伤相关miR-210沉默ISCU1/2抑制线粒体代谢；1.2 miR-210上调沉默E2F3导致P53激活和角质形成细胞增殖抑制；1.3 miR-210上调沉默ACVR1B阻碍角质形成细胞迁移。目的2：确定缺血诱导miR-210的分子机制；中心假设：创伤缺血通过HIF1和乳酸诱导角质形成细胞miR-210。2.1缺氧诱导的miR-210表达由HIF-1/ARNT和新型共激活剂共同驱动；2.2乳酸驱动miR-210的表达。目的3：在标准的临床护理环境下，缺血型人创缘组织表皮miR-210的升高与不良的愈合结果有关。我们建议进行一项前瞻性的纵向研究，纳入到俄亥俄州立大学综合创伤中心就诊的成年非糖尿病慢性小腿溃疡患者。