ALCOHOL AND IMPAIRED LIVER REGENERATION: EFFECTS ON MITOGENIC SIGNALING PATHWAYS

经常饮酒的患者从肝脏损伤中恢复的速度很慢，因为酒精会毒害肝脏的再生能力(重新生长)。因此，酒精性肝病患者死亡率高，住院时间长。申请者得到了NHMRC的支持，以研究酒精如何损害肝脏再生。他们发现，这种影响是在控制肝脏再生的生长因子的细胞表面受体水平上产生的。酒精会改变这些受体的功能。一项重大发现是，它损害了细胞内产生钙升高的能力，这是任何细胞分裂和自我繁殖所必需的。因此，当钙的升高是人为产生的(用化学物质来解锁内部钙储存)时，酒精喂养的大鼠的肝细胞再次在生长因子的影响下做出正常反应并自我复制。目前的工作是为了找出钙的这种效应是在哪里发挥的。研究人员认为，这与其他类型的信号如何工作有关，即所谓的蛋白激酶途径。这些都是一种蛋白质启动(激活)下一种蛋白质的级联，最终开启控制细胞生长的基因。他们将在培养中操纵酒精喂养的大鼠的肝细胞，以确定这些途径中的哪一条受到的影响最大，以及哪一条对控制细胞分裂基因最关键。这些研究将极大地促进我们对酒精如何损害肝脏再生的理解。他们将对肝细胞生长和分裂的控制提供新的见解，这是肝脏对损伤的关键反应，对肝脏的生存至关重要。这类知识将为设计能够控制肝脏生长的新疗法打开大门--在肝脏中毒时重新打开它，或者在它过于旺盛且容易患肝癌时关闭它。

Patients who regularly consume alcohol are slow to recover from liver injury because alcohol poisons the liver's capacity to regenerate itself (grow back). Hence patients with alcohol-induced liver disease have a high mortality and prolonged hospital stays. The applicants have been supported by NHMRC to study how alcohol impairs liver regeneration. They found that the effect is at the level of cell surface receptors for the growth factors that control liver regeneration. Alcohol alters the function of these receptors. One major discovery has been that it damages the capacity to generate a rise in calcium within the cell, something that is fundamentally required for any cell to divide and reproduce itself. Thus when a rise in calcium was produced artificially (with chemicals to unlock the internal calcium stores), liver cells from alcohol-fed rats once more responded normally under the influence of growth factors and replicated themselves. The present work isdesigned to find out where this effect of calcium is exerted. The investigators believe that it is related to how other types of signals work, the so-called protein kinase pathways. These are cascades of one protein turning on (activating) the next down the line to ultimately switch on the genes that control cell growth. They will manipulate liver cells from alcohol-fed rats in culture to establish which of these pathways is most affected, and which is the most critical for the control of cell division genes. These studies will greatly advance our understanding about how alcohol impairs liver regeneration. They will give new insight into the control of liver cell growth and division that is such a crucial response of the liver to injury, vital for survival of the liver. This kind of knowledge will open the door for new treatments to be designed that can control liver growth - turn it back on when it has been poisoned, or turn it off when it is inappropriately vigorous and predisposing to liver cancer.