Investigation of how RNA-directed feedback loops coordinate wound healing and regeneration

PROJECT SUMMARY/ABSTRACT Life is dependent on the fundamental process of cellular migration for fertility, proper embryonic development, and wound healing/regeneration. Developmental transitions during embryonic, fetal, and post-natal maturation in metazoans are tightly controlled via a subset of conserved pathways characterized as heterochronic gene regulators, which regulate the rate and timing of development. Many of the same genes required for embryonic morphogenesis are also required for normal adult stem cell regeneration and wound healing. The long-term goal of our lab is to understand how positive and negative developmental regulatory loops between RNA processing proteins (RPP) and their downstream RNAs (microRNA and mRNA) control wound-healing/regeneration/cell migration. Previous investigations of developmental timing in worms, flies, and frogs have mainly focused on state transitions of stem cells from proliferative to differentiated states or during metamorphosis. Little is understood regarding the combined spatiotemporal regulation of normal adult wound repair and regeneration particularly, in mammals. Synchronization of cell fate and cell migration in the early embryo is an example of where heterochronic genes are key to proper mammalian development via spatiotemporal regulation. Our central hypothesis is developmental pathways that regulate proper morphogenesis are similarly engaged during normal adult wound- repair/regeneration. We propose certain injury conditions, may challenge normal wound repair and regeneration via spatial and/or temporal dysregulation of developmental feedback loops leading to incomplete repair or fibrosis. The objective of this grant is to investigate heterochronic pathways that participate in RNA-directed feedback loops during wound-healing and regeneration. Investigation into how these same heterochronic pathways is conserved or altered during wound-repair and regeneration of will be done using 1) primary and immortalized normal human epithelial cells and 2) established mouse models fibrosis.