HYPOXIA INDUCIBLE FACTOR-1. & DELAYED WOUND HEALING

描述（由申请人提供）： 研究者是弗朗西斯科加州大学整形外科副教授。他对导致正常和延迟伤口愈合的细胞机制感兴趣，特别是因为它涉及糖尿病和转录因子缺氧诱导因子-1（HIF-1）。使用小鼠模型，他正在研究糖尿病如何改变伤口中葡萄糖，乳酸盐，胰岛素或IGF-1的水平，并可能损害HIF-1a蛋白合成，降低HIF-1调节基因（VEGF，HO-1，NOS 2）的表达和延迟愈合。他将（目标1）在瘦素受体缺陷（db/db）的2型糖尿病小鼠及其非糖尿病同窝仔中，将HIF-1a蛋白水平、转录因子活性、几种HIF-1调节蛋白（VEGF、HO-1、NOS 2）的表达和伤口愈合联系起来。他提出：a）增加或减少来自糖尿病皮肤的真皮成纤维细胞中的HIF-1 a蛋白水平与HIF-1转录活性以及培养物中VEGF、HO-1和NOS 2的表达的可比变化相关，B）增加或减少糖尿病和非糖尿病小鼠伤口中的HIF-1 a蛋白导致HIF-1转录活性的相似变化，糖尿病伤口中增加HIF-1a水平加速愈合，而非糖尿病伤口中降低HIF-1a水平延迟愈合。他还将（目标2）研究糖尿病伤口环境中葡萄糖、乳酸盐、胰岛素或IGF-1水平的改变如何影响HIF-1a并延迟伤口愈合。他提出a）细胞上葡萄糖、乳酸盐、胰岛素或IGF-1的生理相关水平模拟伤口环境并改变HIF-1 a水平和功能，B）操纵葡萄糖、乳酸盐、胰岛素或IGF-1浓度伤口改变HIF-1 a水平并影响愈合，c）葡萄糖、乳酸盐、胰岛素、或IGF-1抑制HIF-1 α的蛋白质翻译。确定糖尿病引起的HIF-1通路的改变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.