ALPHA-1 ADRENORECEPTOR, RAS P21, AND LIVER REGENERATION

ALPHA-1 肾上腺素受体、RAS P21 和肝脏再生

• 批准号: 3437952
• 负责人: JENNIFER L CRUISE
• 金额: $ 10.69万
• 依托单位: UNIVERSITY OF ST. THOMAS
• 依托单位国家: 美国
• 财政年份: 1990
• 资助国家: 美国
• 起止时间: 1990-06-01 至 1993-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3437952
• 关键词: DNA replication; G protein; alpha adrenergic receptor; cell growth regulation; epidermal growth factor; laboratory rat; liver cells; liver regeneration; model; norepinephrine; protein kinase C; protooncogene; second messengers; tissue /cell culture

We have demonstrated that the alpha l-adrenergic receptor acts directly on rat hepatocytes to enhance stimulated DNA synthesis (SCIENCE 227:749-51 (1985)), and that this receptor is also involved in the early stimulation of regenerative DNA synthesis in rat liver after 2/3 partial hepatectomy. At a crucial time in the prereplicative phase, the alpha 1 receptor is uncoupled from turnover of membrane phosphatidylinositol (its usual second messenger pathway), and it appears that this form of the receptor is responsible for growth-regulating activities. Additionally, in regenerating liver, this uncoupling is preceded by a fall in immunoreactive membrane p2l, the product of the ras family of cellular proto-oncogenes. The proposed project would examine the mechanism of stimulation by the alpha adrenergic receptor in rat hepatocellular growth, to understand the significance of receptor uncoupling, to seek other second messenger pathways used by these receptors, and to determine to what degree two models of hepatocyte proliferation (liver regeneration in vivo and alpha, stimulated DNA synthesis in primary culture) are comparable. These studies would also examine the role of p2l proteins in both models, and explore whether a link exists between one or more of them and the alpha 1 receptor. The ubiquitous nature of the alpha 1 receptor in tissues, the recent identification of similar receptors as oncogene products (e.g. angiotensin and serotonin receptors) and the still mysterious role of the ras proteins, genes for which are among the most commonly activated of oncogenes in human cancers, suggest that this will be a singularly valuable model to study.

我们已经证明，α l-肾上腺素能受体直接作用于 大鼠肝细胞以增强受刺激的DNA合成（SCIENCE 227：749-51 （1985）），并且该受体也参与早期刺激。 2/3肝部分切除后大鼠肝再生DNA合成的影响。 在复制前阶段的关键时刻，α 1受体 与膜磷脂酰肌醇的周转（其通常的第二次 信使途径），而且似乎这种形式的受体是 负责生长调节活动。此外，在 再生肝脏，这种解偶联之前是下降， 免疫反应膜p2 l，ras家族的产物， 原癌基因 拟议的项目将研究 α肾上腺素能受体在大鼠肝细胞生长中的作用，以了解 受体解偶联的意义，寻找其他第二信使 这些受体使用的途径，并确定在何种程度上两个 肝细胞增殖模型（体内肝再生和α， 原代培养物中刺激的DNA合成）具有可比性。这些研究 还将研究p2 l蛋白在两种模型中的作用，并探索 其中一个或多个与阿尔法1之间是否存在联系 受体的 α 1受体在组织中无处不在的性质， 作为致癌基因产物的类似受体的鉴定（例如血管紧张素 和5-羟色胺受体）以及RAS仍然神秘的作用 蛋白质，基因，其中最常见的激活， 人类癌症中的癌基因，表明这将是一个独特的 有价值的模型来研究。