CANCER AND CHROMOGRANIN A

癌症和嗜铬粒蛋白 A

• 批准号: 3079810
• 负责人: SAMUEL Scott MURRAY
• 金额: $ 6.53万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-08-01 至 1992-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3079810
• 关键词: calcitonin; complementary DNA; disease /disorder model; endocrine neoplasm; hormone regulation /control mechanism; human subject; lung neoplasms; messenger RNA; molecular oncology; neoplasm /cancer diagnosis; peptide hormone; peptide hormone biosynthesis; radioimmunoassay; secretion; small cell lung cancer; thyroid neoplasm; tissue /cell culture

Chromogramin A (CgA) is a high MW protein that is found in essentially all human endocrine tissue. It is co-secreted with the specific hormone form each tissue in both its normal and malignant state. Because it is secreted in excess by endocrine tumors, CgA is an emerging serum marker for endocrine cancers. However, very little is known about the regulation of CgA synthesis and secretion and consequently no provocative about the regulation of CgA synthesis an descretion and consequently no provocative tests for it have been developed. We propose to study the biosynthesis and secretion of CgA and compare it to that of one of its associated hormones, calitonin (CT), in cells that produce both substances. This will be accomplished in cell lines established in our laboratory that are representative of three types of endocrine cancer. One cell line is derived form thyroidal C-cells (medullary thyroid carcinoma) and thus produces CgA and CT eutopically. The other cell lines are derived from lung tumors and thus produce CgA and CT ectopically, one from a classical and one from a variant small cell carcinoma of the lung. We shall study the regulation and the co-regulation of the secretion of CgA and CT by these cells in culture. The secretagogues to be studied include minerals, neuroendocrine mediators, and peptide hormones. The role of "second messengers" will be evaluated by testing the effects of forskolin, phorbol esters, and ionophores. Secretion of CgA and CT will be evaluated by radiommunoassays for the two substances which have been developed in our laboratories. The regulation of the bio-synthesis and transcription of CgA will also be studied. This will be accomplished by pulse- chase labeling experiments and through the use of cDNA probes developed in our laboratory to quantitate CgA-specific mRNAs. These probes will thus be applied to regulatory studies of the molecular biology of CgA using recombinant DNA procedures. This information about CgA regulation will facilitate our clinical goal which is to develop provocative tests for CgA and thus refine the use of the measurement of serum levels of CgA as a tumor marker in the diagnosis and management of patients with the large number of endocrine tumors. The RIA will be applied to studies of patients with the large number of endocrine tumors, including neuroendocrine lung cancer, for which CgA is a potential serum marker. These basic and clinical studies should help us to elucidate the fundamental and clinical significance of CgA in endocrine cancer.

Chromogramin A（CgA）是一种高分子量蛋白，存在于 基本上所有的人体内分泌组织。 它与 在正常组织和正常组织中， 恶性状态 因为它是由内分泌过度分泌的 CgA是一种新兴的内分泌癌症血清标志物。 然而，对CgA的调控知之甚少 合成和分泌，因此没有挑衅性的 调节CgA合成和排泄，因此没有 已经开发了针对它的挑衅性测试。 我们建议研究 CgA的合成和分泌，并将其与 它的一种相关激素，降钙素（CT），在细胞中， 生产这两种物质。 这将在细胞系中完成 在我们的实验室中建立了三个代表性的 内分泌癌的类型 一个细胞系来源于甲状腺 C细胞（甲状腺髓样癌），从而产生CgA和 局部CT。 其他的细胞系来源于肺肿瘤 从而产生CgA和CT异位，一个来自经典的 另一个来自变异的小细胞肺癌。 我们将 研究CgA分泌的调节及协同调节 和CT。 待研究的促分泌素 包括矿物质、神经内分泌介质和肽 荷尔蒙 “第二信使”的作用将由 测试毛喉素、佛波醇酯和离子载体的效果。 CgA和CT的分泌将通过放射免疫分析进行评价 对于我们已经开发的两种物质， laboratories. 生物合成和转录的调控 CGA也将被研究。 这将通过脉冲来实现- chase标记实验和通过使用cDNA探针 在我们的实验室开发的定量CgA特异性mRNA。 因此，这些探针将被应用于 使用重组DNA程序的CgA的分子生物学。 关于CgA调节的信息将有助于我们的临床研究。 目标是开发CgA的挑衅性测试，从而完善 使用CgA血清水平的测量作为肿瘤 在诊断和管理患者的标志物， 大量的内分泌肿瘤。 RIA将适用于 大量内分泌肿瘤患者的研究， 包括神经内分泌肺癌，其中CgA是一种 潜在的血清标志物。 这些基础和临床研究应 帮助我们阐明的基本和临床意义 内分泌癌中的CgA。