MOLECULAR MECHANISMS IN ACANTHOSIS NIGRICANS

黑棘皮病的分子机制

• 批准号: 2856117
• 负责人: GARY A BELLUS
• 金额: $ 10.58万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-05-01 至 2004-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2856117
• 关键词: SCID mouse; acanthosis nigricans; apoptosis; biological signal transduction; biopsy; cell differentiation; cell proliferation; clinical research; epidermal growth factor; fibroblast growth factor; fibroblasts; gene expression; gene mutation; growth factor receptors; human subject; immunocytochemistry; in situ hybridization; insulinlike growth factor; keratinocyte; laboratory mouse; melanocyte; molecular pathology; organ culture; receptor expression; skin

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.

黑色素沉着症（AN）是一种常见的皮肤病，其特征在于表皮中角质形成细胞的异常分化和过度增殖以及真皮中的结构改变。 我们假设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生长因子受体（例如IGFR、EGFR和FGFR）的不适当刺激所致，这些生长因子受体通常起指导表皮分化和再生的作用。 我们建议使用AN作为模型，以更好地了解角质形成细胞增殖和分化的调节生长因子受体信号。 这将通过以下方式实现：1.）使用免疫组织化学和原位杂交技术来表征不同类型AN的皮肤活检中分化特异性角质形成细胞基因表达的改变; 2.）评估表达内源性或转染的FGFR突变的培养的角质形成细胞、黑素细胞和成纤维细胞中生长参数和基因表达的改变;和3.）尝试在皮肤等效器官培养模型中使用表达FGFR突变的角质形成细胞和成纤维细胞或通过操纵培养基中的生长因子来重现AN表型。这些研究将提供一个更好的了解各种生长因子受体信号通路如何影响角质形成细胞增殖和分化的途径，并应提供洞察伤口愈合和其他异常角质形成细胞增殖和分化的疾病，如牛皮癣，皮脂腺性角化病和皮肤癌。