ADRENO RECEPTOR LIVER CARCINOGENESIS AND REGENERATION

拟议研究的目的是调查A1的作用 肾上腺素能受体与肝再生和癌变A1 肾上腺素能受体属于钙动员受体类 通过刺激PIP2周转来发挥细胞调节作用， 其次是二酰甘油和IP3的释放。我们最初展示的是 去甲肾上腺素(NE)刺激EGF诱导的血清有丝分裂 通过A1肾上腺素能受体的游离肝细胞培养。在更多方面 我们最近的研究发现了以下几点： 去甲肾上腺素部分抑制转化生长因子β的丝裂原抑制作用 在正常肝细胞上，特别是在从 2/3肝部分切除后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。它的前面有一个 肝细胞质膜中ras蛋白的尖锐支撑和 二酰甘油细胞质水平的评价。 C.特异性拮抗剂阻断A1肾上腺素能受体 哌唑嗪导致DNA合成峰值大幅下降 肝部分切除后24小时。 D.哌唑嗪对A1肾上腺素能受体的阻断作用 早期肿瘤灶的形成和促进肿瘤的数量和生长 GGT+在苯巴比妥促肝细胞早期癌灶形成中的作用 协议。 E.在促进肝脏肿瘤方面，A1阻断抑制DNA 与增生性增生性疾病相关的合成 苯巴比妥和α-六氯环己烷，但不影响DNA 由过氧化物酶增殖物刺激的合成。 上述调查结果(在本提案中详细描述)需要进一步 肝脏A1肾上腺素能受体作用方式的研究 再生和致癌。我们会进行研究，研究 A1阻断时肝脏再生的机制。的行动模式 A1肾上腺素能受体将在肝细胞培养中进行探索 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细胞相比。A1在正常人群中的作用 肝细胞将与早期肿瘤细胞中的细胞进行比较。这个 A1阻断对早期癌性肝细胞生长的影响 作为兼性干细胞也将被研究。A1的影响 作为促进肝脏肿瘤的一个组成部分的刺激或阻断也将 被调查。最近的研究表明，c-onc的对应物 是血管紧张素II的受体。鉴于 血管紧张素II，类似于去甲肾上腺素，也通过 一种钙动员受体，并作为几个有丝分裂的放大器 细胞类型，上述发现证明了调查的可能性 A1肾上腺素能受体可能具有潜在的细胞功能 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.