Description:
OBJECTIVE: Using a wound/repair animal model that is relevant to humans, elaborate the mechanism by which the various molecules involved in wound healing and repair (e.g. Polycomb Gene Group Proteins and associated demethylases) induce the repair transcriptome (including cell-cycle regulators, matrix molecules, integrins, proteases and antioxidant enzymes). Use the finding to develop diagnostic tests that assess the progress of wound repair and develop a plan for novel therapies that will enhance recovery. DESCRIPTION: Wound and tissue repair and restoration is of critical importance to the returning warfighter. Approaches to repair are actively being studied using stem cell biology and engineering. Epigenetic approaches have great potential but to date are not being actively investigated in the context of wound healing and repair. Epigenetics refers to changes in phenotype (appearance) or gene expression caused by mechanisms other than changes in the underlying DNA sequence, hence the name epi- (Greek: over; above) -genetics. These changes may or may not remain through cell divisions. However, there is no change in the underlying DNA sequence of the organism; instead, non-genetic factors cause the organism's genes to behave (or"express themselves") differently. The ability to direct the wounding/acute response/inflammatory/immune, repair and regenerative pathways following injury could provide a critical path in wound care for the individual at crucial time(s) in the process. Epigenetic changes can be induced in a number of ways. DNA methylation and post-translational modification of histones are the most widely studied examples. Additional small molecules can participate in epigenetic processes by covalent modification of histone proteins including acetylation, ubiquitylation, phophoylation, etc. The ability of small noncoding RNA molecules to induce epigenetic changes is also being increasingly studied. More recently, it has become clear that epigenetic mechanisms are used to respond to changes in the cell nucleus during development and more recently during wound healing and repair. Additional investigation into the molecular details of epigenetic changes during wound healing and repair may shed additional light on this process and inform us on ways to better treat the wounded warfighter immediately and during recuperation. PHASE I: Phase 1 would comprise the identification of small molecules that would initiate, propagate, or sustain repair and or resilience of particular cells or tissues following injury or during embryogenesis. Initial focus could be on the Polycomb Group Protein model to understand the various genes and proteins involved in the repair process, but does not have to be limited to this model. PHASE II: Phase II would identify candidate molecules that could be pursued in animal models. These molecules could be used as diagnostic tools to assess the quality of repair and developed in assays to evaluate therapeutic molecules. PHASE III DUAL USE APPLICATIONS: This phase would provide proof of principle in animal models including one non rodent species. This phase would involve a required pre-meeting with the FDA. REFERENCES: 1) Adrian Bird (2007). Perceptions of epigenetics. Nature 447: 396398 2) Ingela Djupedal and Karl Ekwall (2009) Epigenetics: heterochromatin meets RNAi. Cell Research 19:282-295. 3) Tanya Shaw and Paul Martin (2009). Epigenetic reprogramming during wound healing: loss of polycomb-mediated gene silencing may enable upregulation of repair genes. EMBO reports, 10 (8): 881-886
