REGULATION OF EPIDERMAL DIFFERENTATION BY PTHRP

描述：(改编自申请者的摘要)-皮肤由 有两个不同的层次：表皮和真皮。最外层，即 表皮由称为角质形成细胞的细胞组成，角质形成细胞经历 被称为分化的细胞变化，以产生持久的水- 和抗菌屏障。下面的真皮由称为 提供胶原平台和生长因子的成纤维细胞 对角质形成细胞的增殖和分化起调节作用。 真皮也向表皮发出信号，以产生毛发、汗腺和指甲。 在他们适当的地方。真皮功能障碍被认为是一种 皮肤病理的组成部分，包括伤口愈合障碍，一些表皮 癌症和皮肤老化。似乎存在着分子间的交换 表皮和真皮对这两个细胞层的功能至关重要。 人们对这些分子以及它们如何发挥作用知之甚少。 功能。角质形成细胞产生的一种这样的分子似乎可以调节 成纤维细胞的功能是甲状旁腺激素相关蛋白(PTHrP)。这 这项提议是基于最近产生的转基因小鼠的发现 缺乏甲状旁腺素受体。这些小鼠患有严重的皮肤病，可能代表着 皮肤过早老化。根据以下文件中包含的初步证据 这一建议提出了以下假设：角质形成细胞来源 N-末端甲状旁腺激素rP通过旁分泌信号调节表皮分化 通过真皮成纤维细胞表达的经典PTH/PTHrP受体介导， 从而产生影响经济增长的增长因素 基底层角质形成细胞的增殖/分化。 这一假设将在以下具体目标中得到检验： 1)检测胎儿皮肤甲状旁腺素受体及甲状旁腺素/甲状旁腺素受体的表达， 新生、成年和老年小鼠2)决定分子和细胞机制 PTHrP信号在皮肤中的作用。3)确定N-末端甲状旁腺素受体基因的作用。 真皮成纤维细胞在体外和体内的增殖和功能。

DESCRIPTION: (Adapted from the applicant's abstract) - The skin is made up of two distinct layers: the epidermis and dermis. The outermost layer, the epidermis, is composed of cells called keratinocytes that undergo regulated cellular changes known as differentiation in order to produce a durable water- and germ-resistant barrier. The underlying dermis is composed of cells called fibroblasts that provide the collagen platform as well as the growth factors necessary for the regulated proliferation and differentiation of keratinocytes. The dermis also signals the epidermis to produce hair, sweat glands, and nails in their proper places. Dysfunction of the dermis is speculated to be a component of skin pathologies including wound healing disorders, some epidermal cancers, and skin aging. It appears there is an exchange of molecules between epidermis and dermis that is crucial to the function of both cellular layers. Very little is known about these molecules and how they perform their functions. One such molecule produced by keratinocytes that appears to regulate fibroblast function is parathyroid hormone related-protein (PTHrP). This proposal is based upon findings from a recently-generated transgenic mouse that lacks PTHrP. These mice have a severe skin disorder that may represent premature skin aging. On the basis of preliminary evidence contained within this proposal the following hypothesis is suggested: Keratinocyte-derived N-terminal PTHrP regulates epidermal differentiation by paracrine signaling mediated through classical PTH/PTHrP receptors expressed on dermal fibroblasts, resulting in the production of growth factors that influence the proliferation/differentiation of basal keratinocytes. This hypothesis will be tested in the following specific aims: 1) Determine PTHrP and PTH/PTHrP receptor expression in skin of fetal, neonatal, adult, and aged mice 2) Determine molecular and cellular mechanisms of PTHrP signaling in skin. 3) Determine the effect of N-terminal PTHrP on dermal fibroblast proliferation and function in vitro and in vivo.