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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Center Core Grants (P30)
Project #
5P30AR057217-05
Application #
8499268
Study Section
Special Emphasis Panel (ZAR1-KM-D)
Project Start
Project End
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
5
Fiscal Year
2013
Total Cost
$24,966
Indirect Cost
$9,362
Name
University of Pennsylvania
Department
Type
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Wong, Waihay J; Richardson, Theresa; Seykora, John T et al. (2015) Hypoxia-inducible factors regulate filaggrin expression and epidermal barrier function. J Invest Dermatol 135:454-61
Hammers, Christoph M; Chen, Jing; Lin, Chenyan et al. (2015) Persistence of anti-desmoglein 3 IgG(+) B-cell clones in pemphigus patients over years. J Invest Dermatol 135:742-9
Thangapazham, Rajesh L; Klover, Peter; Li, Shaowei et al. (2014) A model system to analyse the ability of human keratinocytes to form hair follicles. Exp Dermatol 23:443-6
Cho, Michael Jeffrey; Lo, Agnes S Y; Mao, Xuming et al. (2014) Shared VH1-46 gene usage by pemphigus vulgaris autoantibodies indicates common humoral immune responses among patients. Nat Commun 5:4167
Rangel, Javier R; Chung, Yoonjie; Rosenbach, Misha et al. (2014) Expression of Notch signaling components in cutaneous foreign body and sarcoidal granulomas and fusing macrophages. Am J Dermatopathol 36:409-13
Rashighi, Mehdi; Agarwal, Priti; Richmond, Jillian M et al. (2014) CXCL10 is critical for the progression and maintenance of depigmentation in a mouse model of vitiligo. Sci Transl Med 6:223ra23
Mao, Xuming; Li, Hong; Sano, Yasuyo et al. (2014) MAPKAP kinase 2 (MK2)-dependent and -independent models of blister formation in pemphigus vulgaris. J Invest Dermatol 134:68-76
Guan, Hancheng; Nuth, Manunya; Zhukovskaya, Natalia et al. (2014) A novel target and approach for identifying antivirals against molluscum contagiosum virus. Antimicrob Agents Chemother 58:7383-9
Suzuki, Daisuke; Leu, N Adrian; Brice, Angela K et al. (2014) Expression analysis of Dact1 in mice using a LacZ reporter. Gene Expr Patterns 15:21-30
Thangapazham, Rajesh L; Klover, Peter; Wang, Ji-an et al. (2014) Dissociated human dermal papilla cells induce hair follicle neogenesis in grafted dermal-epidermal composites. J Invest Dermatol 134:538-40

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