HYPOXIA INDUCIBLE FACTOR-1. & DELAYED WOUND HEALING

描述(由申请人提供)： 这位研究员是旧金山加州大学整形外科的副教授。他对导致正常和延迟伤口愈合的细胞机制感兴趣，特别是与糖尿病和转录因子缺氧诱导因子-1(HIF-1)有关的机制。利用小鼠模型，他正在研究糖尿病如何改变伤口中葡萄糖、乳酸、胰岛素或IGF-1的水平，并可能损害HIF-1a蛋白质合成，减少HIF-1调节基因(血管内皮生长因子、HO-1、NOS2)的表达，从而延迟愈合。他将(目标1)将HIF-1a蛋白水平、转录因子活性、几种HIF-1调节蛋白(血管内皮生长因子、HO-1、NOS2)的表达与瘦素受体缺陷(db/db)2型糖尿病小鼠及其非糖尿病小鼠的伤口愈合联系起来。他提出，a)糖尿病皮肤来源的真皮成纤维细胞中HIF-1a蛋白水平的增加或减少与HIF-1转录活性的类似变化有关，并且在培养的HIF-1中表达的VEGF、HO-1和NOS2；b)糖尿病和非糖尿病小鼠伤口中HIF-1a蛋白的增加或减少会导致类似的HIF-1转录活性的变化；c)糖尿病创面中HIF-1a水平的升高促进愈合，而非糖尿病创面中HIF-1a水平的降低则延迟愈合。他还将(目标2)研究糖尿病伤口环境中葡萄糖、乳酸、胰岛素或IGF-1水平的变化如何影响HIF-1a并延迟伤口愈合。他提出，a)细胞上生理上相关的葡萄糖、乳酸、胰岛素或IGF-1水平模拟伤口环境，改变HIF-1a水平和功能；b)操纵伤口葡萄糖、乳酸、胰岛素或IGF-1浓度改变HIF-1a水平并影响愈合；c)糖尿病伤口环境中葡萄糖、乳酸、胰岛素或IGF-1水平的改变抑制HIF-1a的蛋白质翻译。识别糖尿病引起的HIF-1通路的变化，可能会改善这些问题伤口的治疗。

DESCRIPTION (provided by applicant): 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-1a 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-1a 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-1a 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-1a protein in the diabetic and non-diabetic mouse wounds results in similar changes of HIF-1 transcriptional activity, c) Increasing HIF-1a levels in diabetic wounds accelerate healing and decreasing HIF-1a 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-1a 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-1a levels and function, b) Manipulating glucose, lactate, insulin, or IGF-1 concentrations wounds alters HIF-1a 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-1a. Identifying alterations in the HIF-1 pathway due to diabetes, may lead to improved therapy for these problem wounds.