Tissue Oxygenation and Wound Healing

组织氧合和伤口愈合

• 批准号: 8514903
• 负责人: Chandan K Sen
• 金额: $ 29.9万
• 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 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8514903
• 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; Functional RNA; 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; 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; public health relevance; 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（由申请人提供）： 摘要已知伤口组织的氧合状态通过多种机制影响伤口结果，包括促进氧化代谢、对抗感染、羟基化胶原蛋白、产生一氧化氮以及产生可支持氧化还原的活性氧。慢性缺血性伤口的病因通常是多因素的，其中由潜在的外周血管病变引起的缺氧通常被认为是一个常见因素。那么，为什么缺血性伤口不能更快地闭合呢？尽管缺氧可能对内皮细胞产生有利影响，但缺氧诱导的转录因子 HIF 会特异性诱导角质形成细胞生长停滞，从而损害伤口闭合。我们的观察直接表明缺氧诱导的 microRNA (miRNA) 或hypoxamir 抑制角质形成细胞功能，具体来说，我们注意到hypoxamir miR-210 会沉默会阻止生长的靶基因。在小鼠和慢性伤口患者中，缺血性伤口的 miR-210 水平升高。我们筛选了会损害伤口再上皮化的 miR-210 依赖性途径，我们研究了小鼠研究中出现的候选途径与人类慢性伤口的相关性，并使用人类慢性伤口成功验证了这些途径。该提案选择了边缘组织进行研究，它代表了一类最近发现的非编码（nc）基因，它们是否对人类健康和疾病具有非凡的意义。功能性或沉默是由针对该组基因的特定 miR 决定的。当我们寻求将组织氧合和伤口愈合的研究带向未来时，我们选择重点揭示hypoxamir miR-210 在调节伤口闭合方面的重要性。建议： 目标 1：表征缺血性伤口的 miR-210 依赖性受损伤口再上皮化的潜在机制。 1.1 缺血性伤口相关的 miR-210 升高使 ISCU1/2 沉默，抑制线粒体代谢； 1.2 miR-210升高沉默E2F3导致p53激活并抑制角质形成细胞增殖； 1.3 miR-210 上调沉默 ACVR1B，阻碍角质形成细胞迁移 目标 2：确定缺血诱导 miR-210 的分子机制；中心假设：伤口缺血通过 HIF1 诱导角质形成细胞 miR-210。和乳酸。 2.1 HIF-1¿ /ARNT 和新型共激活剂驱动缺氧诱导的 miR-210 表达； 2.2 乳酸驱动 miR-210 表达 目标 3：缺血性人类伤口边缘组织表皮中 miR-210 升高与标准临床护理环境下的不良愈合结果相关。患有慢性腿部溃疡并前往 OSU 综合伤口中心就诊的患者将被纳入。