Hair follicle bulge cells in tumorigenesis and alopecia

描述（由申请人提供）：该项目的长期目标是更好地了解上皮干细胞生物学。上皮干细胞负责自我更新组织的再生，如表皮、毛囊和角膜。我们最初在毛囊凸起处发现了假定的上皮干细胞。然后，我们在转基因小鼠中分离出一个角蛋白15启动子，该启动子针对凸起细胞。K15启动子可用于毛囊干细胞的分离、谱系分析和分子表征。我们发现，膨出细胞具有干细胞的特性，分离的膨出细胞可以重建毛囊、表皮和皮脂腺。我们现在已经确定了一些我们假设维持干细胞表型的基因。在这项拨款申请中，我们会：

DESCRIPTION (provided by applicant): The long term goal of this project is to better understand epithelial stem cell biology. Epithelial stem cells are responsible for the regeneration of self-renewing tissues such as epidermis, hair follicle, and cornea. We originally identified putative epithelial stem cells in the bulge of the hair follicle. We then isolated a keratin 15 promoter that targets bulge cells in transgenic mice. The K15 promoter allowed for the isolation, lineage analysis and molecular characterization of hair follicle stem cells. We showed, that bulge cells have properties of stem cells, and isolated bulge cells can reconstitute hair follicles, epidermis and sebaceous glands. We have now identified a number of genes which we hypothesize maintain the stem cell phenotype. In this grant application we will: 1. evaluate whether genes upregulated in the bulge cells are important for maintaining the hair follicle stem cell phenotype by: a. overexpressing candidate genes in non-hair follicle stem cells of transgenic mice, and then testing whether these cells behave as hair follicle stem cells. b. blocking candidate gene pathways specifically in the bulge cells using our Kl5CrePrl mice to delete or overexpress genes specifically in the bulge cells. 2. determine if genes downregulated in telogen bulge cells are involved in stem cell activation and/or lineage determination by: a. generating inducible transgenic mice in which candidate genes are over-expressed in bulgecells using an RU486 inducible system, and b. deleting candidate "bulge activation" or lineage determining genes specifically in bulge cells and their progeny using theKlSCrePR l mice. 3. develop means for isolating and characterizing human hair follicle stem cells. a. We will establish whether genes identified in mouse bulge are also expressed in human bulges. b. We will delineate hair follicle stem and progenitor cells within both the mouse and human hair follicle based on cell surface protein expression patterns. These distinct subpopulations of cells within the hair follicle will be isolated by fluorescent activated cell sorting, and their stem cell nature, gene expression patterns and functional characteristics will be discerned. Patients with alopecia, hair shaft disorders, basal cell carcinoma, hair follicle tumors, or chronic wounds could potentially benefit from this research.