HYPOXIA INDUCIBLE FACTOR-1. & DELAYED WOUND HEALING

缺氧诱导因子-1。

• 批准号: 6942728
• 负责人: DAVID M YOUNG
• 金额: $ 25.79万
• 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/6942728
• 关键词: diabetes mellitus; enzyme linked immunosorbent assay; fibroblasts; gene expression; genetic transcription; glucose; hypoxia inducible factor 1; immunocytochemistry; insulin; insulinlike growth factor; laboratory mouse; lactates; leptin; nitric oxide synthase; protein biosynthesis; tissue /cell culture; transcription factor; transfection; vascular endothelial growth factors; wound healing

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.

描述（由申请人提供）： 研究人员是旧金山加州大学分校的整形手术副教授。他对导致正常和延迟伤口愈合的细胞机制感兴趣，尤其是与糖尿病有关，转录因子缺氧诱导因子1（HIF-1）。使用小鼠模型，他正在检查伤口中糖尿病如何改变糖尿病，乳酸，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-HO-1，NOS 2）的表达和延迟愈合。他将（AIM 1）将HIF-1A蛋白的水平，转录因子的活性，几种HIF-1调控蛋白（VEGF，HO-1，NOS 2）的表达以及瘦素受体缺陷型（DB/DB）2型糖尿病小鼠中的伤口愈合及其伤口愈合。他提出a）糖尿病皮肤的真皮成纤维细胞中的HIF-1A蛋白水平增加或降低与HIF-1转录活性的可比变化以及VEGF，HO-1和NOS 2在培养中的表达相当糖尿病伤口可加速愈合，并在非糖尿病伤口中降低HIF-1A水平会延迟愈合。他还将（AIM 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。 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伤口环境抑制HIF-1A的蛋白质翻译。确定由于糖尿病引起的HIF-1途径的改变，可能会改善这些问题伤口的治疗。