Studies of Normal and Neoplastic Human Pituitaries

正常和肿瘤性人类垂体的研究

• 批准号: 6514932
• 负责人: Ricardo Vincent Lloyd
• 金额: $ 23.42万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-05-15 至 2006-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6514932
• 关键词: adenoma; carcinogenesis; cell cycle proteins; cell differentiation; chromogranins; clinical research; cyclin dependent kinase; enzyme inhibitors; gene induction /repression; hormone receptor; human subject; immunocytochemistry; in situ hybridization; leptin; neoplastic growth; neoplastic process; neuropeptides; pituitary gland; pituitary neoplasms; protein kinase

Pituitary neoplasms are associated with a great deal off morbidity of excessive hormone production and/or as space occupying lesions in the central nervous system. The mechanisms regulating pituitary tumor growth in humans are poorly understood. Recent studies have shown that pituitary adenomas are monoclonal and that some specific genetic alterations are present in these tumors. However, very little is known about the regulation of the pituitary tumor growth and why only few of these neoplasms become malignant, which usually leads to the patient's demise in spite of aggressive treatment. Our laboratory has recently developed human pituitary cell lines immortalized with a replication-defective recombinant human adenovirus which should provide stable cell lined for many of the proposed studies. We plan to examine the mechanisms regulating pituitary growth and tumor progression using cell and molecular biological approaches. Preliminary studies indicate that pancreastain, a proteolytic product of chromogranin, which is processed by PC 1/3 and PC 2 in pituitary cells, has autocrine and paracrine regulatory functions on pituitary tumor cells. Our preliminary studies also showed that pancreastain inhabits cell proliferation in vitro. The haploid insufficiency paradigm will be explored to possibly explain some of the effects of p27 on pituitary tumor development and progression. Our laboratory was the first to discover leptin production and secretion by anterior pituitary cells. We also noted that leptin inhabit plan to examine the mechanism of leptin action in the pituitary. The specific aims include: I. Determine the role of chromogranin/secretogranin proteolytic products and neuroendocrine-specific proconvertases in pituitary tumor growth and differentiation. II. Determine the role of specific cell cycle inhibitors in the development of pituitary tumors. a. Examine the mechanism regulating p27 expression in pituitary tumor development and progression. b. Determine the role of p16 methylation in pituitary tumor development. III. Examine the role of leptin, leptin receptors, STAT and SOCS proteins in pituitary tumor development and progression. The information derived from these studies should provide insight into the pathobiology of pituitary tumors and lead to more effective treatment modalities.

垂体肿瘤与过量激素产生和/或作为中枢神经系统中占据损害的空间的发病率很大。对人类垂体肿瘤生长的调节的机制知之甚少。最近的研究表明，垂体腺瘤是单克隆的，并且在这些肿瘤中存在一些特定的遗传改变。然而，对于垂体肿瘤生长的调节以及为什么这些肿瘤中只有很少的恶性肿瘤的调节知之甚少，这通常会导致患者的灭亡，尽管接受了积极的治疗。我们的实验室最近开发了使用复制缺陷的重组人腺病毒永生的人垂体细胞系，该细胞应为许多拟议的研究提供稳定的细胞。我们计划使用细胞和分子生物学方法检查调节垂体生长和肿瘤进展的机制。初步研究表明，胰腺的蛋白水解产物胰腺产物在垂体细胞中由PC 1/3和PC 2处理，在垂体肿瘤细胞上具有自分泌和旁分泌调节功能。我们的初步研究还表明，胰腺体外栖息在细胞增殖中。单倍体功能不全将被探讨，以解释p27对垂体肿瘤发育和进展的某些影响。我们的实验室是第一个发现垂体前细胞产生瘦素和分泌的实验室。我们还注意到，瘦素居住在垂体中瘦素作用的机制。具体目的包括：I。确定嗜铬粒蛋白/分泌蛋白蛋白水解产物和神经内分泌特异性的proconvertases在垂体肿瘤生长和分化中的作用。 ii。确定特定细胞周期抑制剂在垂体肿瘤发展中的作用。一个。检查调节垂体肿瘤发育和进展中p27表达的机制。 b。确定p16甲基化在垂体肿瘤发育中的作用。 iii。检查瘦素，瘦素受体，STAT和SOCS蛋白在垂体肿瘤发育和进展中的作用。从这些研究中得出的信息应提供对垂体肿瘤病理生物学的见解，并导致更有效的治疗方式。