Investigating the Genetic Makeup of Non-Healing Wounds
Another important aspect of understanding characteristics of wounds that fail to heal involves analyzing their genetic makeup. Wound healing is a complex, multi-step process that involves highly coordinated interactions among cell regulatory pathways. Every step in these pathways is regulated by gene activity. Modern methods of genome-wide analysis enable the simultaneous evaluation of thousands of genes, and these methods can be used to identify groups of genes that are involved in the wound healing process. If we can identify genes that are specifically associated with healing deficits in chronic wounds, then we can start to develop targeted therapies to improve wound repair.
Our research findings about the genetic characteristics of non-healing wounds include the following:
- The finding that β-catenin—a multifunctional protein that plays an important role during embryonic development—appears to accumulate abnormally in the cell nuclei of chronic venous ulcers that fail to heal.
- Identifying a set of microRNAs—small molecules of ribonucleic acid that regulate gene expression in the cell nucleus—that are expressed abnormally in chronic venous ulcers, and developing small molecules that can target these microRNAs in the cell..
- The finding that c-myc—a gene that is required for normal cell division, but that gets activated abnormally in some types of cancer—is induced at the non-healing edge of all types of ulcers, where it inhibits the normal migration of new skin cells across the wound—an essential part of the healing process. As a result of this research, c-myc is one of the first genes to be confirmed as impairing the healing process—a landmark discovery. Gene expression analysis also revealed that, among other changes, glucocorticoid treatment induced the changes in c-myc gene expression that we expected based on our tissue studies of c-myc.
- Finally, we found different gene expression patterns in tissue from the non-healing edge of the raw wound and in the healing-competent rim that is left after surgical debridement. These differences can be used to identify specific genes that are involved in the normal process of skin repair.
An NIH-funded project, on which Dr. Brem is a co-principal investigator, is currently underway to validate β-catenin and c-myc as markers of wound healing in diabetic foot ulcers, and to identify additional cellular markers that can help us identify wounds that are not likely to respond to standard wound treatment and need aggressive targeted treatment.