Studies of Normal and Neoplastic Human Pituitaries

垂体肿瘤与激素分泌过多和/或中枢神经系统占位性病变的发病率有很大关系。调节人类脑下垂体肿瘤生长的机制还知之甚少。最近的研究表明，垂体腺瘤是单克隆性的，在这些肿瘤中存在一些特殊的基因改变。然而，对垂体肿瘤生长的调节以及为什么这些肿瘤中只有少数变成恶性的原因知之甚少，这通常会导致患者死亡，尽管进行了积极的治疗。我们实验室最近建立了用复制缺陷的重组人腺病毒永生化的人垂体细胞系，这将为许多拟议的研究提供稳定的细胞线。我们计划使用细胞和分子生物学方法来研究调节脑下垂体生长和肿瘤进展的机制。初步研究表明，在垂体细胞中，嗜铬粒蛋白经PC 1/3和PC 2处理后产生的蛋白水解物胰蛋白酶对垂体瘤细胞具有自分泌和旁分泌调节功能。我们的初步研究还表明，胰淀素在体外抑制细胞增殖。单倍体不足范例将被探索，以可能解释p27在垂体瘤发生和发展中的一些作用。本实验室首次发现垂体前叶细胞产生和分泌瘦素。我们还注意到瘦素抑制计划研究瘦素在脑下垂体中的作用机制。具体目标包括：1.确定嗜铬粒蛋白/分泌颗粒蛋白分解产物和神经内分泌特异性前转化酶在垂体肿瘤生长和分化中的作用。确定特异性细胞周期抑制物在垂体肿瘤发生发展中的作用。1.探讨p27基因在垂体肿瘤发生发展中的调控机制。B.确定p16甲基化在脑垂体瘤发生中的作用。研究瘦素、瘦素受体、STAT和SOCS蛋白在垂体肿瘤发生发展中的作用。从这些研究中获得的信息应该有助于深入了解垂体瘤的病理生物学，并导致更有效的治疗方式。

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.