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.

摘要：众所周知，伤口组织的氧合状态会通过多种机制影响伤口的预后，包括促进氧化代谢、抵抗感染、羟基化胶原蛋白、产生一氧化氮和产生可能支持氧化还原信号的活性氧。慢性缺血性伤口的病因通常是多因素的，其中潜在的周围血管病变引起的缺氧是一个常见的因素。缺氧通常被认为是血管生成的因素。那么为什么缺血的伤口不能更快愈合呢？虽然缺氧可能对内皮细胞有有利的影响，但缺氧诱导的转录因子HIF特异性地诱导角化细胞生长停滞，影响伤口愈合。HIF1¿在伤口边缘的基底角化细胞中含量丰富，并导致生长停滞。我们的观察结果直接暗示了缺氧诱导的microRNA （miRNA）或低氧蛋白在抑制角质形成细胞功能中的作用。具体来说，我们注意到低xamir miR-210沉默了抑制生长/迁移以及抑制角质形成细胞线粒体代谢的靶基因。在小鼠和慢性伤口患者中，缺血性伤口显示miR-210水平升高。接下来，我们筛选了miR-210依赖性通路，这些通路会损害伤口再上皮化。我们研究了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在人类慢性伤口边缘组织中成功验证的特定途径被选择用于本提案的研究。microRNA （miR或miRNA）代表了一类最近发现的非编码（nc）基因，它们对人类健康和疾病具有非凡的意义。一组编码基因是否具有功能或沉默是由针对该组基因的特异性mir决定的。当我们寻求将组织氧合和伤口愈合的研究带到未来时，我们选择重点揭示低氧amir miR-210在调节伤口闭合中的意义。提出了三个目的：目的1：表征miR-210依赖性缺血伤口再上皮化的机制。1.1缺血损伤相关miR-210沉默ISCU1/2抑制线粒体代谢的升高；1.2升高的miR-210沉默E2F3，导致p53活化，抑制角质细胞增殖；1.3 miR-210上调沉默ACVR1B，阻碍角质细胞迁移。目的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¿和乳酸诱导角化细胞miR-210。2.1 HIF-1 /ARNT和新型共激活因子驱动缺氧诱导的miR-210表达；2.2乳酸驱动miR-210表达。目的3：在标准临床护理环境下，缺血人伤口边缘组织表皮miR-210升高与愈合效果差有关。我们提出了一项前瞻性纵向研究，其中成人非糖尿病慢性腿部溃疡患者访问俄勒冈州立大学综合伤口中心将被纳入。