The skin forms an essential permeability barrier that protects internal organs and tissues from physical damage, dehydration, pathogen invasion, and other harmful environmental stresses. Defective barrier function is associated with a broad range of pathologies including chronic wounds, congenital diseases, epithelial cancers, infection, and other inflammatory conditions. In order to understand the basis of these disease states, it is vital to first understand the processes by which the epidermis forms during development. The skin arises from a single layer of stem cell progenitors to become a functionally specialized, multi-layered permeability barrier at birth via a process of rapid expansion and differentiation. What are the quality control mechanisms that act to ensure tissue function is optimized during development in preparation for post-natal life? A phenomenon known as cell competition has been proposed to act as a selection mechanism in rapidly expanding tissues, whereby less fit ?loser? cells are eliminated by fitter neighbouring ?winner? cells. The extent to which cell competition acts as a conserved regulator of tissue and organ growth is unknown. This study sets out to test the hypothesis that in the mammalian skin, cell competition provides an essential quality control mechanism during development to safeguard the tissue against stresses in both pre- and post-natal life. Using a unique combination of genetic tools available in the mouse, the proposed work employs a combination of cell biology, lineage tracing and computational approaches to uncover evidence for cell competition during epidermal development (Aim 1). Furthermore, building on a newly established system to experimentally induce cell competition, functional genetics and quantitative live imaging will be used to dissect the genetic regulation of cell competition (Aim 2). Finally, using functional assays, the proposed experiments examine the consequence of disrupting cell competition during development on the ability of the skin to carry out its essential barrier function (Aim 3). The expected results will (a) establish a new paradigm and generate genetic tools to study mammalian cell competition; (b) offer new perspective on spatiotemporal control of early epidermal development; (c) shed light on the molecular underpinnings of cell competition, which may be exploited therapeutically in the long term to treat a broad range of barrier pathologies. Under the supervision of leading epidermal cell biologist, Dr. Elaine Fuchs, the co-mentorship of cell competition expert, Dr. Laura Johnston, and the stimulating training environment at the Rockefeller University, I am ideally positioned to fully develop my technical skills, knowledge, and leadership. My research, training, and career development will allow me to establish a unique research niche in epidermal and developmental biology as an independent investigator.
The skin is the body's first line of defense against a wide range of environmental stresses. This proposal employs an innovative, multi-scale, interdisciplinary approach to identify the quality control mechanisms that maximize the ability of the skin to respond and recover from challenges that arise as a result of such stresses. Understanding the genetic underpinnings of these mechanisms will yield avenues for novel therapeutic strategies to promote barrier function in congenital disease, wound healing, inflammatory disorders, and cancer.
