FETAL SKIN BIOLOGY

我们以前对正常和异常人类发育的研究 皮肤已经记录了各种表达的变化， 分化特异性标记物与细胞的形态学相协调。 组织.这项工作提供了一个连贯的图片皮肤 发展和确定的事件和发展时期， 据推测，这对建立正常成人的模板至关重要， 皮肤我们现在更加重视理解的研究 影响这些变化的细胞相互作用的种类 描述并将解决细胞与细胞和组织相互作用的作用 调节皮肤的形态发生和分化。这类 最好的例子是表皮细胞的形成 因此，本提案的重点是形成 毛囊皮脂腺结构我们使用的是一个很好的系统 可以直接在体内（新鲜组织）和实验中进行研究， 体外（细胞培养、器官培养、移植）。我们开发了 悬浮器官培养，其可重复地支持形成， 表皮附属物的继续发育（见初步数据和 附录）长达60天，并保持，并允许增长， 表皮和真皮以明显正常的方式。我们不知道 任何其他具有这种潜力的人类皮肤培养系统。这 文化系统将用于确定 诱导、起始、生长、分化和维持 表皮附属物在发育中的人类皮肤，并确定 上皮细胞（角质形成细胞）和间充质细胞在 互动。我们将重点关注生长因子（NGF， EGF，POGF，TGF-8）及其受体（其中一些特别 影响上皮细胞，其他细胞特异于间充质细胞 细胞）、基质成分（1、111、V和VI型胶原蛋白;纤连蛋白 和胶原酶），其它相关分子（例如，米诺地尔）和神经 毛囊发育中的纤维。受影响患者的皮肤 X连锁少汗性外胚层发育不良，一种遗传性疾病， 附件形成的发育和出生后异常是 疾病的标志，将进行研究，以确定是否 任何生长因子等被确定为在 附肢的个体发育在成体组织中异常表达。

Our previous studies of the development of both normal and abnormal human skin have documented changes in the expression of various differentiation-specific markers coordinate with the morphology of the tissue. This work has provided a coherent picture of cutaneous development and identified events and periods of development which are presumed to be critical in establishing the template of the normal, adult skin. We are now placing more emphasis in our studies on understanding the kinds of cellular interactions that occur to effect the changes described and will address the role of cell-cell and tissue interactions in modulating niorphogenesis and differentiation of the skin. These kinds of interactions are best exemplified in the formation of epidermal appendages, hence the focus of this proposal on the formation of pilosebaceous structures. We are using a very well characterized system that can be studied directly in vivo (fresh tissue) and experimentally in vitro (cell culture, organ culture, grafting). We have developed the suspension organ culture which supports, reproducibly, the formation and continued development of epidermal appendages (see preliminary data and appendix) for as long as 60 days and maintains, and permits growth, of epidermis and dermis in an apparently normal manner. We are unaware of any other human skin culture system which has this potential. This culture system will be used to identify the requirements for the induction, initiation, growth, differentiation and maintenance of epidermal appendages in developing human skin, and to determine the presumptive roles of epithelial (keratinocytes) and mesenchymal cells in the interaction. We will focus on parts played by growth factors (NGF, EGF, POGF, TGF-8) and their receptors (some of which specifically influence epithelial cells, others which are specific for mesenchymal cells), matrix components (collagen types 1, 111, V and VI; fibronectin and collagenase), other relevant molecules (e.g., minoxidil) and nerve fibers in hair follicle development. Skin from patients affected with X-linked hypohidrotic ectodermal dysplasia, a genetic disorder in which development and postnatal abnormalities of appendage formation are the hallmark of the diseases, will be studied in order to determine whether any of the growth factors, etc. identified to be important in the ontogeny of appendages are abnormally expressed in the adult tissue.