Project Summary
My long-term career goal is to become a successful independent investigator in the field of
musculoskeletal regenerative medicine, developing therapeutics to promote the regeneration of complex tissues
after injury or disease. The objective of this proposal is to help me transition to independence by providing me
with critical scientific skills to investigate the cellular and molecular mechanisms of murine digit tip regeneration
versus fibrotic scarring. To reach this objective, a thorough training plan has been established, including research
aims and tailored training activities. The proposed research project will seek to develop a novel mouse model
and an induced pluripotent stem cell (iPSC) in vitro culture system in order to dissect the functional role of
regulatory genes involved in embryonic limb development and morphogenesis, including Hox genes. The central
hypothesis of the proposal is that HoxA cluster genes, and specifically Hoxa13, are required during digit
regeneration to coordinate osteogenic differentiation, outgrowth, and patterning via Eph/ephrin and bone
morphogenetic protein (BMP) signaling. We will investigate this hypothesis by conditionally deleting HoxA cluster
genes from osteoblast lineage cells in transgenic mice in Aim 1 and by modulating Hoxa13 gene expression in
iPSCs in vitro using a lentiviral-mediated approach in Aims 2 and 3a. Finally, we will evaluate the therapeutic
potential of Hoxa13-expressing cells delivered to the wound site of non-regenerative digits in Aim 3b. The project
outlined in this application combines basic science with a clinically relevant in vivo platform and cutting-edge
transcriptomic and bioinformatic technologies to query the gene regulatory networks and signaling pathways that
lead to regeneration versus scarring after musculoskeletal injury. This proposal also includes a comprehensive
series of educational activities that will prepare me for my independent research faculty position. The world-class
institutional environment at Washington University in St. Louis provides a multitude of resources to ensure the
successful completion of the proposed work, as well as ample opportunities for career development. Finally, the
assembled Scientific and Career Advisory Committee, along with new mentoring relationships that I am fostering
in the developmental and regenerative biology communities, will monitor research progress, provide constructive
feedback, and advocate for my professional development as I begin my independent research career.