HYPOXIA INDUCIBLE FACTOR-1. & DELAYED WOUND HEALING

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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.