REGULATION OF EPIDERMAL DIFFERENTATION BY PTHRP

描述：（改编自申请人摘要）-皮肤由以下成分组成： 有两层表皮和真皮最外层， 表皮由称为角质形成细胞的细胞组成， 细胞变化称为分化，以产生持久的水- 和抗细菌屏障。下面的真皮是由细胞组成的， 成纤维细胞提供胶原平台以及生长因子 调节角质形成细胞的增殖和分化所必需的。 真皮也向表皮发出信号，以产生毛发、汗腺和指甲 在适当的地方。据推测，真皮功能障碍是 皮肤病理学的组成部分，包括伤口愈合障碍，一些表皮 癌症和皮肤老化。看起来在两个人之间 表皮和真皮，其对两个细胞层的功能至关重要。 关于这些分子以及它们如何发挥作用的知之甚少。 功能协调发展的角质形成细胞产生的一种这样的分子， 成纤维细胞功能是甲状旁腺激素相关蛋白（PTHrP）。这 该建议是基于最近产生的转基因小鼠的发现， 缺乏PTHrP。这些老鼠有一种严重的皮肤病， 皮肤过早老化。根据初步证据， 该提议提出了以下假设：角质细胞来源的 N端PTHrP通过旁分泌信号调节表皮分化 通过在真皮成纤维细胞上表达的经典PTH/PTHrP受体介导， 导致生长因子的产生， 基底角质形成细胞的增殖/分化。 将在以下具体目标中检验这一假设： 1)测定胎儿皮肤中PTHrP和PTH/PTHrP受体的表达， 新生、成年和老年小鼠2）确定分子和细胞机制 PTHrP信号传导。3)确定N-末端PTHrP对 真皮成纤维细胞增殖和功能的体外和体内研究。

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.