Acanthosis nigricans (AN) is a common skin disorder characterized by abnormal differentiation and hyperproliferation of keratinocytes in the epidermis and structural changes in the dermis. We hypothesize that the AN phenotype results from inappropriate stimulation of several different growth factors receptors expressed in keratinocytes and fibroblasts (eg IGFR, EGFR and FGFRs) which normally function to direct epidermal differentiation and regeneration. We propose to use AN as a model to better understand the regulation of keratinocyte proliferation and differentiation by growth factor receptor signaling. This will be accomplished by: 1.) using immunohistochemical and in situ hybridization techniques to characterize alterations in the expression of differentiation specific keratinocyte genes in skin biopsies of different types of AN; 2.) assessing alterations in growth parameters and gene expression in cultured keratinocytes, melanocytes and fibroblasts expressing endogenous or transfected FGFR mutations; and 3.) attempting to recapitulate the AN phenotype in a skin equivalent organ culture model using either keratinocytes and fibroblasts expressing FGFR mutations or by manipulation of growth factors in the culture media. These studies will provide a better understanding of how various growth factor receptor signaling pathways influence keratinocyte proliferation and differentiation pathways and should provide insights into wound healing and other disorders of abnormal keratinocyte proliferation and differentiation such as psoriasis, sebhorreic keratoses and skin cancer.
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