MOLECULAR MECHANISMS IN ACANTHOSIS NIGRICANS

黑棘皮病是一种常见的皮肤病，以表皮角质形成细胞异常分化、过度增殖和真皮结构改变为特征。我们推测，AN表型是由于角质形成细胞和成纤维细胞中表达的几种不同的生长因子受体(如IGFR、EGFR和FGFRs)的不适当刺激造成的，这些受体通常具有指导表皮分化和再生的功能。我们建议使用AN作为一个模型，以更好地了解生长因子受体信号对角质形成细胞增殖和分化的调控。这将通过以下方式实现：1.应用免疫组织化学和原位杂交技术研究不同类型AN皮肤组织中分化特异性角质形成细胞基因表达的变化。评估培养的角质形成细胞、黑素细胞和表达内源性或转基因FGFR突变的成纤维细胞的生长参数和基因表达的变化；试图通过使用角质形成细胞和表达FGFR突变的成纤维细胞或通过操纵培养液中的生长因子来概括皮肤等同器官培养模型中的AN表型。这些研究将更好地了解各种生长因子受体信号通路如何影响角质形成细胞的增殖和分化途径，并将为伤口愈合和其他角质形成细胞异常增殖和分化的疾病，如银屑病、脂溢性角化病和皮肤癌提供见解。

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.