ADRENO RECEPTOR LIVER CARCINOGENESIS AND REGENERATION

这项研究的目的是探讨A1在 肾上腺素能受体在肝再生和癌变中的作用 A1 肾上腺素能受体属于钙动员受体 其通过刺激PIP 2周转而发挥细胞调节作用， 随后释放二酰基甘油和IP 3。 我们最初展示了 去甲肾上腺素（NE）刺激EGF诱导的有丝分裂 游离肝细胞培养物通过A1肾上腺素能受体。 更 最近的研究发现： A.去甲肾上腺素部分抑制TGF β的有丝分裂抑制作用 对正常肝细胞，特别是对从 2/3肝部分切除术后10 ~ 20小时再生肝。 B。肝脏对A1肾上腺素能受体的敏感性增加 再生与A1的解偶联有关。 它的前面是一个 ras蛋白在肝细胞质膜上的尖锐突起， 二酰基甘油的细胞质水平的评价。 C.特异性拮抗剂对A1肾上腺素能受体的阻断作用 哌唑嗪导致DNA合成峰值显著降低， 部分肝切除术后24小时。 D.哌唑嗪对A1肾上腺素能受体的阻断作用 早期肿瘤灶的发展，并增加肿瘤的数量和生长， 苯巴比妥促进肝细胞GGT+早期肿瘤灶 议定书 E.与肝肿瘤促进相关，A1阻断抑制DNA 在增生性增生期间观察到的合成， 苯巴比妥和六氯环己烷，但不会影响DNA 由过氧化物酶体增殖物刺激的合成。 上述调查结果（在本提案中有详细说明）证明， 肝脏A1肾上腺素能受体作用方式的研究 再生和致癌作用。 将对以下方面进行研究： A1阻断期间的肝再生机制。 的作用模式 A1肾上腺素能受体将在肝细胞培养物中探索， 在整个动物研究中。 A1在正常肝细胞中的性质将 与早期肿瘤细胞中的那些相比。 A1在正常人中的作用 将肝细胞与早期肿瘤细胞中的肝细胞进行比较。 的 阻断A1对早期肿瘤肝细胞生长的影响 作为兼性干细胞也将被研究。 A1的影响 作为肝肿瘤促进组分的刺激或阻断也将 追究 最近的研究表明，c-onc对应物 是血管紧张素II的受体。 考虑到 事实上，血管紧张素II，类似于去甲肾上腺素， 一种钙动员受体，并作为一个促有丝分裂放大器， 细胞类型，上述发现保证了调查的可能性， A1肾上腺素能受体可能作为细胞的一种功能， 肝肿瘤的原癌基因。

The purpose of the proposed research is to investigate the role of the A1 adrenergic receptor in liver regeneration and carcinogenesis. A1 adrenergic receptor belongs to the group of calcium mobilizing receptors which exert cell regulatory influences by stimulation of PIP2 turnover, followed by release of diacylglycerols and IP3. We had originally shown that norepinephrine (NE) stimulates mitogenesis induced by EGF in serum free hepatocyte cultures through the A1 adrenergic receptor. In more recent studies we have found the following: A. Norepinephrine partially inhibits the mito-inhibitory effect of TGF beta on normal hepatocytes and especially on hepatocytes obtained from regenerating liver between 10 to 20 hours after 2/3 partial hepatectomy. B. The increased sensitivity to A1 adrenergic receptor during liver regeneration is associated with uncoupling of the A1. It is preceded by a sharp prop of the ras protein in the hepatocyte plasma membrane and evaluation of cytoplasmic levels of diacylglycerols. C. Blockade of the A1 adrenergic receptor by the specific antagonist prazosin causes a substantial decrease in the peak of DNA synthesis seen at 24 hours after partial hepatectomy. D. Blockage of the A1 adrenergic receptor by prazosin stimulates development of early neoplastic foci and enhances the numbers and growth of GGT+ early neoplastic foci of hepatocytes in the phenobarbital promotion protocol. E. In relation to hepatic tumor promotion, A1 blockage inhibits DNA synthesis seen during the augmentative hyperplasia associated with phenobarbital and a-Hexachlorocyclohexane but it does not affect the DNA synthesis stimulated by peroxisome proliferators. The above findings (described in detail in this proposal) warrant further investigation of the mode of action of the A1 adrenergic receptor in liver regeneration and carcinogenesis. Studies will be conducted on the mechanisms of liver regeneration during A1 blockage. The mode of action of A1 adrenergic receptor will be explored in hepatocyte cultures as well as in whole animal studies. The properties of A1 in normal hepatocytes will be compared to those in early neoplastic cells. The effect of A1 in normal hepatocytes will be compared to those in early neoplastic cells. The effect of A1 blockage on the growth of early neoplastic hepatocytes as well as facultative stem cells will also be studied. The impact of A1 stimulation or blockade as a component of hepatic tumor promotion will also be investigated. It was shown in recent studies that the c-onc counterpart of the oncogene mas is the receptor for angiotensin II. In view of the fact that angiotensin II, similar to norepinephrine, also operates through a calcium mobilizing receptor and act as a mitogenic amplifier for several cell types, the above findings warrant the investigation of the possibility that the A1 adrenergic receptor may potentially function as a cellular proto-oncogene for liver neoplasia.