Mechanisms for Impaired Diabetic Wound Healing

About This Grant

Project Summary The goal of this project is to carry out in vivo studies to understand how type-1 and type-2 diabetes alter oral and skin wound healing. Mechanistic studies are proposed based on exciting Prel Data that blocking permissive histone-3 methylation completely rescues the negative impact of diabetes on gingival and skin healing. These experiments will utilize a highly specific inhibitor, MM-102, that is effective in nanomolar concentrations. A secondary goal is to determine whether the cellular and molecular impact differs in oral and dermal wounds. The proposed experiments will utilize a number of advanced approaches including Chromium single cell RNAseq and Xenium spatial transcriptomics from 10x Genomics. They will also utilize cell sorting followed by CUT&RUN H3K4me3 analysis combined with bulk RNAseq. The different approaches will be integrated through bioinformatic analysis that will facilitate an unbiased examination of diabetes-impaired wound healing combined with a hypothesis-driven mechanistic investigation. In addition, we will carry out translational studies in a large mini-pig animal model to address the therapeutic use of the inhibitor. The experiments are significant since epigenetic changes that regulate specific genes play a key role in "glycemic memory" that alters cell behavior and are grounded in strong Prel Data. A better understanding of this specific epigenetic change and how it regulates gene expression could greatly improve our understanding of diabetic complications and lead to the identification of new therapeutic approaches to diabetic wound healing. Aim 1 will focus on a mechanistic murine studies involving the inhibitor MM-102. Aim 2 encompasses translational studies to determine whether the MM-102 inhibitor improves wound healing in a large, well-established T2D mini-pig animal model. The investigative team includes experts in diabetic wound healing, oral wound healing, skin wound healing, bioinformatics, spatial transcriptomics and murine and porcine diabetic wound healing models.