Defining the role of mutational burden in sustaining normal homeostasis during aging

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Project Summary The skin is a dynamic organ comprised of three main layers, the topmost layer being the epithelium followed by the basement membrane and the dermis. Stem cells within the skin are located within the basal layer which is the innermost layer of the epithelium. Beneath this layer resides the basement membrane which is comprised of various proteins as well as proteoglycans and separates the epithelium from the dermis. The dermis is the innermost layer of the organ and contains numerous different types of cells but is primarily comprised of fibroblasts. These fibroblasts secrete various proteins that are essential for skin structure. We have discovered through DTA ablation and immunofluorescence that these fibroblasts appear to inhibit stem cell proliferation as ablation resulted in hyperproliferative activity of stem cells within the tissue. This relationship highlights the importance of fibroblasts in maintaining skin homeostasis as excess stem cell proliferation has the potential to be detrimental to the skin as it can increase the risk of cancer-causing mutations. The aim of our project is addressing the different mechanisms by which the skin goes about repairing itself, and the effect of the different cellular components have in maintaining skin homeostasis. The aim of our parent grant addresses the major question of “how normal are cell behaviors are properly orchestrated on the single-cell and tissue-scale level during homeostasis as the organism ages. Supplemental funding is requested to support Deandra Simpson for 24 months of postbaccalaureate work to pursue a scientific goal and to prepare for and apply to Medical Scientist Training Programs. Deandra will train and take on responsibility for the different aspects of the research described in the supplemental proposal. As described in the “Research Experience Plan”, Deandra will assist on a project focused on understanding the relationship between fibroblasts and epithelial stem cell proliferation in Aim 1: new approaches to investigate different phenomena that contribute to skin homeostatic control during regeneration and Aim 2: learning how to genetically manipulate our model organism to measure how these changes lead to disruption in skin homeostasis. Our most recent work seemed to demonstrate that the ablation of fibroblasts increases epithelial stem cell proliferation in vivo. However, we still lack a detailed molecular level understanding of the causes of these changes. Different genetic approaches will be used to delineate the mechanism that led to these changes and the overall impact of fibroblasts in maintaining skin homeostasis.