NRF2 Activation in Diabetic Wound Healing

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PROJECT SUMMARY / ABSTRACT For patients with diabetes mellitus (DM), the development of chronic wounds is a life-threatening complication that necessitates over 100,000 lower extremity amputations per year in the U.S. alone. Despite improvements in the management of DM, the treatment of diabetic wounds remains challenging due to the inherent defects in wound healing in diabetic vs. normal skin. Underlying vasculopathies, neuropathies, increased inflammation, and thickened basement membranes due to diabetes predispose the skin to developing non-healing wounds. Moreover, diabetic skin exhibits increased oxidative stress and decreased expression of nuclear factor erythroid 2–related factor 2 (NRF2), a transcription factor that activates a pathway that protects cells from increased oxidative stress. Several studies suggest that NRF2 activation could be a relevant target for the management and prevention of chronic diabetic wounds. The current proposal utilizes novel small molecule NRF2 activators that exhibit increased specificity of binding and decreased mutagenicity relative to existing compounds, without sacrificing solubility, potency, or stability. These novel molecules are an innovative and optimal tool to study the effects of NRF2 activation on diabetic skin. The long-term objective of this work is to develop topically-applied NRF2-activating drugs for the treatment of human chronic diabetic wounds. The goals of the current research are to test the ability of highly specific and novel NRF2 activators to improve diabetic wound healing and to understand their mechanisms of action. In this study, the effects of NRF2 activation on diabetic wound healing will be investigated in db/db mice, a well- characterized in vivo model system of DM. Aim 1A will determine the effects of this novel class of NRF2 activators on wound healing, including wound closure, oxidative stress, and the quality of tissue restoration. Aim 1B will employ whole-tissue RNA-sequencing and functional pathway analysis to investigate the effects of NRF2 activation in diabetic wounds at the transcriptome level. The data will be used to determine which functional pathways regulated by NRF2 are important to diabetic skin pathology. Aim 2 will examine the effects of our candidate molecules on macrophages and investigate whether these novel NRF2 activators act by improving macrophage function in diabetic wound healing. Investigation into the effects of NRF2 activation on diabetic wound healing may lead to the development of a life-saving, effective, and practical drug for patients with chronic diabetic wounds.