CANCER AND HYPERCALCEMIA

这项建议旨在研究生物合成、分泌、细胞- 甲状旁腺激素相关基因的具体加工和表达 甲状旁腺素相关蛋白(PTHrP)与恶性肿瘤高钙血症 免疫化学和核酸杂交程序也可以 用于PTHrP的临床诊断、分型和治疗 产生肿瘤。PTHrP是一种141残基蛋白质，由 通常与高钙血症有关的肿瘤。在前13个氨基酸中 在该蛋白中，有8个与人甲状旁腺激素的氨基末端同源 甲状旁腺素生物活性片段。PTHrP氨基末端片段， PTHrP1-34，与PTH受体反应，产生大部分生物 自然甲状旁腺激素的影响，包括高钙血症。我们已经开发了 细胞和分子生物学研究的实验程序 PTHrP。我们已经开发了几个细胞系，可以产生多个物种 PTHrP mRNAs和PTHrP本身。我们有特定的抗体 在组织和生物体液中鉴定PYHrP，我们就有了核苷酸 探索性研究其基因表达。在免疫组织学研究中，我们有 能够在包括鳞状细胞在内的各种组织中显示甲状旁腺素受体 细胞肺癌和小细胞肺癌。我们建议研究 PTHrP在这些细胞系中的生物合成和分泌 放射免疫分析和相关的免疫化学程序。这个 放射免疫分析程序将另外在两个地点进行 格式，以衡量PTHrP的定义物种。这些化验研究 将与以下规模确定程序一起进行 层析、蛋白质分析和脉冲追逐实验。这个 PTHrP mRNA的调控将通过Northern杂交进行评估。在……里面 除了这些人体组织，我们还开发了动物模型 甲状旁腺素相关蛋白的研究。这些实验工具将允许基本的监管 我们提出的研究。我们还建议研究其临床作用。 甲状旁腺素受体作为新发内分泌癌的组织和血清标志物 开发了基于多表位识别的免疫化学程序。 这些研究应该有助于阐明PTHrP在分子中的作用， 具有内分泌功能的肺癌的细胞生物学和临床生物学 特点。

This proposal is designed to study the biosynthesis, secretion, cell- specific processing, and gene expression of the parathyroid hormone-related protein (PTHrP) associated with the hypercalcemia of malignancy with immunochemical and nucleic acid hybridization procedures that can also be used in the clinical diagnosis, classification, and management of PTHrP- producing tumors. PTHrP is a 141 residue protein that is produced by tumors commonly associated with hypercalcemia. Of the first 13 amino acids of this protein, 8 are homologous to the amino terminus of human PTH, the biologically active fragment of PTH. The amino-terminal fragment of PTHrP, PTHrP1-34, reacts with the PTH receptor and produces most of the biological effects of native PTH, including hypercalcemia. We have developed the experimental procedures to study the cellular and molecular biology of PTHrP. We have developed several cell lines that produce multiple species of PTHrP mRNAS and PTHrP, itself. We have specific antibodies that identify PYHrP in tissues and biological fluids and we have nucleotide probes to study its gene expression. In immunohistology studies, we have been able to demonstrate PTHrP in a variety of tissues, including squamous cell lung cancer and also small-cell lung cancer. We propose to study the biosynthesis and secretion of PTHrP in these cell lines using radioimmunoassay and related immunochemical procedures. The radioimmunoassay procedures will additionally be performed in a two-site format in order to measure defined species of PTHrP. These assay studies will be conducted in conjunction with sizing procedures such as chromatography, Western Analysis, and pulse-chase experiments. The regulation of PTHrP mRNA will be evaluated by Northern hybridization. In addition to these human tissues, we have developed animal models for the study of PTHrP. These experimental tools will permit the basic regulatory studies that we propose. We also propose to study the clinical role of PTHrP as a tissue and serum marker for endocrine cancers with newly developed immunochemical procedures based on multiple epitope recognition. These studies should help elucidate the role of PTHrP in the molecular, cellular, and clinical biology of lung tumors with endocrine characteristics.