PARATHYROID HORMONE-LIKE PEPTIDE FROM KERATINOCYTES

正常人角质形成细胞分泌甲状旁腺激素样肽 (PTH-LP)体外培养。角质形成细胞PTH-LP似乎来源于 与新近克隆的肿瘤来源甲状旁腺激素-LP的同源基因 与体液高钙血症相关的临床证候 恶毒。这种多肽的正常功能尚不清楚：这些因素 调节其在体内的表达尚不清楚。 这项提案的长期目标是：1)确定是否 以及角质形成细胞中这种分子的产生是如何调节的；2) 确定该分子在皮肤中的功能(S)，并阐明 作用机制(S)：3)确定是否存在 皮肤病与其异常表达的关系 分子。 这些目标和假设将在组织切片和 表皮生长分化的组织培养模型与意志 为PTH-LP使用特定的分子和免疫学探针。这个 具体问题是：生产规则：a.哪些角质形成细胞 在表皮内制造和分泌PTH-LP？B.有没有 通过生理或药物途径调节甲状旁腺素-脂蛋白的产生 角质形成细胞？C.调控生产的分子基础是什么？是 在转录、剪接、 翻译、细胞内加工还是分泌？的功能/机制 作用：a.PTH-LP对正常角质形成细胞生长有何影响 和差异化，以及是什么调节了这种影响？假设： 甲状旁腺素-脂蛋白的自分泌作用是通过增加细胞内 钙，然后触发或扩大分化。它是什么？ 对真皮成纤维细胞的影响？假设：该分子在 真皮重塑通过其转化生长因子-β对结缔组织分泌的作用 组织元素。与疾病的关系：a.甲状旁腺素-脂蛋白在 表皮肿瘤性疾病或良性增生性疾病 疾病？如果是，在血清中能检测到PTH-LP吗？B.如果 分子在正常角化中起作用，是否存在角化障碍 甲状旁腺素异常产生或对甲状旁腺素反应引起的角化 LP？

Normal human keratinocytes secrete a parathyroid hormone-like peptide (PTH-LP) in vitro. The keratinocyte PTH-LP appears to be derived from the same gene as the recently cloned cDNA for a tumor-derived PTH-LP associated with the clinical syndrome of humoral hypercalcemia of malignancy. The normal function of this peptide is not known: the factors regulating its expression in vivo are not known. The long-term objectives of this proposal are: 1) to determine whether and how production of this molecule is regulated in keratinocytes; 2) to identify the function(s) of this molecule in the skin and elucidate the mechanism(s) by which it acts: 3) to determine whether there is a relationship between diseases of the skin and abnormal expression of this molecule. These aims and hypotheses will be investigated in tissue sections and in tissue culture models of epidermal growth and differentiation and will employ specific molecular and immunologic probes for the PTH-LP. The specific questions are: Production regulations: a. Which keratinocyts within the epidermis make and secrete the PTH-LP? b. Are there physiologic or pharmacologic ways to regulate production of the PTH-LP by keratinocytes? c. What is the molecular basis of regulated production? Is production regulated at the level of transcription, splicing, translation, intracellular processing or secretion? Function/mechanism of action: a. What effect does the PTH-LP have on normal keratinocyte growth and differentiation and what mediates that effect? Hypothesis: The autocrine action of the PTH-LP acts via an increase in intracellular calcium which then triggers or augments differentiation. b. What are its effects on dermal fibroblasts? Hypothesis: The molecule plays a role in dermal remodelling via its TGF-b like action on secretion on connective tissue elements. Relation to disease: a. Is the PTH-LP overexpressed in neoplastic diseases of the epidermis or in benign hyperproliferative diseases? If so, is the PTH-LP detectable in the serum? b. If the molecule has a role in normal keratinization, are there disorders of keratinization caused by abnormal production of or response to the PTH- LP?