The development of normal skin depends upon the elaborate interaction of numerous cell types derived from ectoderm, neuroectoderm and mesoderm. Nevi and other hamartomas presumably develop when aberrant cellular interactions lead to deposition of cells in inappropriate locations. Factors important for communication between keratinocytes, melanocytes, fibroblasts and other cell types likely orchestrate proper cell positioning and their reactivation in the adult may lead to cancer and metastasis. Determining molecules responsible for induction of benign hamartomas, like blue nevi, is a first step in elucidating the mechanisms of tumor formation and progression. Here we will use a skin reconstitution model in an immunodeficient mouse grafting system to begin to decipher the inductive and inhibitory signals that lead to the formation of a blue nevus. In 1996, Prouty and coworkers found that when they combined specific types of fibroblast cell lines with neonatal epidermal cells and grafted the mixture onto immunodeficient mice, the grafted area developed a common blue nevus (CBN) or a nevus sebaceus of Jadassohn (NSJ) depending on which cells were used. Grafting of epidermal cells alone resulted only in a scar, while combining epidermal cells with fresh whole dermis regenerated normal appearing skin possessing hair follicles, melanocytes and sebaceous glands. In this study we will use gene expression microarrays to compare mesenchymal cell lines that induce blue nevi with those that do not. We plan to identify candidate genes important for the migration, survival and localization of melanocytes. These candidate genes will be stably overexpressed in non-inductive fibroblast cells to test for induction of a blue nevus phenotype. Ultimately, we will evaluate whether blue nevi and other melanocytic hamartomas from humans express the identified genes. The results from these studies will form the foundation for a K-award or new investigator RO1 for Dr. Castelo-Soccio, the principal investigator.
These experiments aim to uncover basic molecular mechanisms regulating mesenchymal-epithelial interactions important for mammalian skin and hair follicle development. The information obtained in these studies has the potential to reveal novel therapeutic targets for epidermal and pigmentary disorders.
|Monteleon, Christine L; Agnihotri, Tanvir; Dahal, Ankit et al. (2018) Lysosomes Support the Degradation, Signaling, and Mitochondrial Metabolism Necessary for Human Epidermal Differentiation. J Invest Dermatol 138:1945-1954|
|Meisel, Jacquelyn S; Sfyroera, Georgia; Bartow-McKenney, Casey et al. (2018) Commensal microbiota modulate gene expression in the skin. Microbiome 6:20|
|Plikus, Maksim V; Guerrero-Juarez, Christian F; Ito, Mayumi et al. (2017) Regeneration of fat cells from myofibroblasts during wound healing. Science 355:748-752|
|Xu, Mingang; Horrell, Jeremy; Snitow, Melinda et al. (2017) WNT10A mutation causes ectodermal dysplasia by impairing progenitor cell proliferation and KLF4-mediated differentiation. Nat Commun 8:15397|
|Cho, Michael Jeffrey; Ellebrecht, Christoph T; Hammers, Christoph M et al. (2016) Determinants of VH1-46 Cross-Reactivity to Pemphigus Vulgaris Autoantigen Desmoglein 3 and Rotavirus Antigen VP6. J Immunol 197:1065-73|
|Hammers, Christoph M; Stanley, John R (2016) Mechanisms of Disease: Pemphigus and Bullous Pemphigoid. Annu Rev Pathol 11:175-97|
|Ellebrecht, Christoph T; Bhoj, Vijay G; Nace, Arben et al. (2016) Reengineering chimeric antigen receptor T cells for targeted therapy of autoimmune disease. Science 353:179-84|
|Geherin, Skye A; Gómez, Daniela; Glabman, Raisa A et al. (2016) IL-10+ Innate-like B Cells Are Part of the Skin Immune System and Require ?4?1 Integrin To Migrate between the Peritoneum and Inflamed Skin. J Immunol 196:2514-2525|
|Lo, Agnes S; Mao, Xuming; Mukherjee, Eric M et al. (2016) Pathogenicity and Epitope Characteristics Do Not Differ in IgG Subclass-Switched Anti-Desmoglein 3 IgG1 and IgG4 Autoantibodies in Pemphigus Vulgaris. PLoS One 11:e0156800|
|Gay, Denise L; Yang, Chao-Chun; Plikus, Maksim V et al. (2015) CD133 expression correlates with membrane beta-catenin and E-cadherin loss from human hair follicle placodes during morphogenesis. J Invest Dermatol 135:45-55|
Showing the most recent 10 out of 97 publications