PARATHYROID HORMONE-LIKE PEPTIDE FROM KERATINOCYTES

正常人角质形成细胞分泌甲状旁腺素样肽 （PTH-LP）。角质形成细胞PTH-LP似乎来源于 与最近克隆的肿瘤源性PTH-LP的cDNA相同的基因 与体液性高钙血症的临床综合征相关， 恶性肿瘤这种肽的正常功能尚不清楚： 调节其在体内的表达是未知的。 本提案的长期目标是：1）确定是否 以及该分子的产生如何在角质形成细胞中调节; 2） 确定这种分子在皮肤中的功能，并阐明 （3）确定是否存在一个或多个 皮肤疾病和这种异常表达之间的关系， 分子。 这些目标和假设将在组织切片和 表皮生长和分化的组织培养模型， 使用针对PTH-LP的特异性分子和免疫学探针。的 具体问题是：生产条例：a.哪些角质细胞 在表皮内产生并分泌甲状旁腺素脂蛋白？B.有 调节PTH-LP产生的生理学或药理学方法， 角质细胞？C.管制生产的分子基础是什么？是 在转录，剪接， 翻译、细胞内加工或分泌？功能/机制 行动：a.甲状旁腺素脂蛋白对正常角质形成细胞的生长有什么影响 以及是什么在调节这种效应？假设：The PTH-LP的自分泌作用通过增加细胞内 钙然后触发或增强分化。B.它有哪些 对皮肤成纤维细胞的影响假设：该分子在 通过其TGF-β样作用对结缔组织分泌的真皮重塑 组织成分与疾病的关系：A。PTH-LP是否在 表皮的肿瘤性疾病或良性过度增殖性疾病 疾病？如果是，血清中是否可检测到PTH-LP？B.如果 分子在正常角质化中起作用，是否有 由PTH的异常产生或对PTH的反应引起的角质化- 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?