HYPOXIA INDUCIBLE FACTOR-1. & DELAYED WOUND HEALING

缺氧诱导因子-1。

• 批准号: 7469705
• 负责人: DAVID M YOUNG
• 金额: $ 7.76万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-01 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7469705
• 关键词: Amputation; Area; Blood; Cells; Chronic; Dermal; Developed Countries; Developing Countries; Diabetes Mellitus; Diabetic mouse; Diabetic wound; Disruption; Environment; Fibroblasts; Gene Targeting; Genetic Transcription; Glucose; Growth Factor; Healed; Homeostasis; Hyperglycemia; Impaired wound healing; Insulin; Insulin-Like Growth Factor I; Lead; Leg; Metabolic; Metabolism; Nitric Oxide Synthase; Oxygen; Pathway interactions; Patients; Personal Satisfaction; Plastic Surgical Procedures; Play; Process; Protein Biosynthesis; Proteins; Research Personnel; Role; San Francisco; Skin; Translations; VEGFA gene; Vascular Endothelial Growth Factors; Wound Healing; angiogenesis; diabetic; diabetic wound healing; genetic regulatory protein; glycation; healing; hypoxia inducible factor 1; improved; interest; leptin receptor; mouse model; non-diabetic; professor; programs; transcription factor; wound

The investigator is an Associate Professor of Plastic Surgery at UC, San Francisco. He is interested in the cellular mechanisms that lead to normal and delayed wound healing especially as it pertains to diabetes and the transcription factor hypoxia inducible factor-1 (HIF-1). Using a mouse model he is examining how diabetes alters levels of glucose, lactate, insulin, or IGF-1 in the wound and may impair HIF-lo_ protein synthesis, decreased expression of HIF-1 regulated genes (VEGF, HO-1, NOS 2) and delayed healing. He will (Aim 1) correlate the levels of HIF-I_ protein, activity of the transcription factor, expression of several HIF-1 regulated proteins (VEGF, HO-1, NOS 2), and wound healing in leptin receptor-deficient (db/db) Type 2 diabetic mice and their non-diabetic littermates. He proposed that a) Increasing or decreasing HIF-lo_ protein levels in dermal fibroblasts derived from diabetic skin is associated with a comparable change in HIF-1 transcriptional activity, and expression of VEGF, HO- 1 and NOS 2 in culture, b) Increasing or decreasing HIF-I_ protein in the diabetic and non-diabetic mouse wounds results in similar changes of HIF-1 transcriptional activity, c) Increasing HIF-lo_ levels in diabetic wounds accelerate healing and decreasing HIF-I(_ levels in non-diabetic wounds delays healing. He also will (Aim 2) investigate how the altered levels of glucose, lactate, insulin, or IGF-1 in the diabetic wound environment influence HIF-I(_ and delay wound healing. He proposes that a) Physiologically relevant levels of glucose, lactate, insulin, or IGF-1 on cells mimic the wound environment and alter HIF-I_ levels and function, b) Manipulating glucose, lactate, insulin, or IGF-1 concentrations wounds alters HIF-I(_ levels and influences healing, c) Altered levels of glucose, lactate, insulin, or IGF-1 found in the diabetic wound environment inhibit protein translation of HIF-I(_. Identifying alterations in the HIF-1 pathway due to diabetes, may lead to improved therapy for these problem wounds.

研究者是旧金山加州大学整形外科副教授。他感兴趣的是 导致伤口正常愈合和延迟愈合的细胞机制，尤其是与糖尿病有关的细胞机制 和转录因子缺氧诱导因子-1 (HIF-1)。 他使用小鼠模型研究糖尿病如何改变小鼠体内的葡萄糖、乳酸、胰岛素或 IGF-1 水平。 伤口并可能损害 HIF-lo_ 蛋白质合成，降低 HIF-1 调节基因（VEGF、 HO-1，NOS 2) 和延迟愈合。他将（目标 1）将 HIF-I_ 蛋白的水平与 转录因子、多种 HIF-1 调节蛋白（VEGF、HO-1、NOS 2）的表达和伤口 瘦素受体缺陷 (db/db) 2 型糖尿病小鼠及其非糖尿病同窝小鼠的愈合。他 提出 a) 增加或减少源自糖尿病的真皮成纤维细胞中的 HIF-lo_ 蛋白水平 皮肤与 HIF-1 转录活性以及 VEGF、HO- 表达的类似变化相关。 培养物中的 1 和 NOS 2，b) 糖尿病和非糖尿病小鼠中 HIF-I_ 蛋白的增加或减少 伤口导致 HIF-1 转录活性的类似变化，c) 糖尿病患者 HIF-lo_ 水平增加 伤口加速愈合并降低非糖尿病伤口中的 HIF-I(_ 水平会延迟愈合。他还 将（目标 2）研究糖尿病伤口中葡萄糖、乳酸、胰岛素或 IGF-1 水平的变化 环境影响 HIF-I(_ 并延迟伤口愈合。他提出 a) 生理相关水平 细胞上的葡萄糖、乳酸、胰岛素或 IGF-1 模拟伤口环境并改变 HIF-I_ 水平， b) 控制葡萄糖、乳酸、胰岛素或 IGF-1 浓度伤口会改变 HIF-I(_ 水平和 影响愈合，c) 糖尿病伤口中葡萄糖、乳酸、胰岛素或 IGF-1 水平的改变 环境抑制 HIF-I(_. 识别糖尿病引起的 HIF-1 通路的改变可能会改善这些疾病的治疗 问题伤口。