REGULATION OF EPIDERMAL DIFFERENTATION BY PTHRP

PTHRP 对表皮分化的调节

• 批准号: 6511941
• 负责人: JOHN Gregory FOLEY
• 金额: $ 24.72万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-05-03 至 2005-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6511941
• 关键词: age difference; aging; animal old age; cell cell interaction; cell differentiation; cell proliferation; fibroblasts; growth factor; hormone receptor; hormone regulation /control mechanism; infant animal; keratinocyte; laboratory mouse; paracrine; parathyroid hormone related protein; receptor expression; skin; tissue /cell culture

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.

描述：（改编自申请人的摘要）- 皮肤由以下材料组成 两个不同的层：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，这些细胞受到调节 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 提供胶原蛋白平台和生长因子的成纤维细胞 角质形成细胞的增殖和分化的调节所必需的。 真皮还向表皮发出信号，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、某些表皮 癌症、皮肤老化。看来之间存在分子交换 表皮和真皮对于两个细胞层的功能都至关重要。 人们对这些分子以及它们如何发挥作用知之甚少 功能。一种由角质形成细胞产生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 该提案基于最近产生的转基因小鼠的发现 缺乏 PTHrP。这些小鼠患有严重的皮肤病，可能代表 皮肤过早老化。根据其中包含的初步证据 该提案提出以下假设：角质细胞衍生 N 端 PTHrP 通过旁分泌信号调节表皮分化 通过真皮成纤维细胞上表达的经典 PTH/PTHrP 受体介导， 从而产生影响生长因子 基底角质形成细胞的增殖/分化。 该假设将在以下具体目标中得到检验： 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 皮肤中 PTHrP 信号传导的研究。 3) 确定N端PTHrP对 真皮成纤维细胞在体外和体内的增殖和功能。