BASES OF CIRRHOSIS IN ALCOHOLIC LIVER DISEASE

描述：这项建议是我们研究的继续，我们的研究试图 阐明酒精性肝病中肝硬变的分子基础。肝脏 酒精滥用或其他原因引起的纤维生成是一个复杂的过程。 这涉及到肝细胞增殖和细胞死亡之间的平衡，因为 以及细胞外基质(ECM)沉积和建模的增加 蛋白质。我们最近的研究为其中一个的重要性提供了证据 因子，组织转谷氨酰胺酶(TTG)，在许多这些相互作用中。这 无处不在的酶具有可诱导细胞或细胞凋亡的特性 增殖，而且它似乎在许多方面促进了纤维化过程。 当然了。这一提议试图阐明tTG的作用机制。 影响肝脏有丝分裂或凋亡的过程，尤其是当 与乙醇管理有关。具体目标：1)确定路径 以及肝细胞中α-1肾上腺素能信号的功能意义； 研究α-1肾上腺素能信号转导通路的下游效应 肝细胞有丝分裂；3)阐明tTGase的作用机制 交联剂活性抑制细胞增殖和促进细胞凋亡 肝细胞。这些研究将需要确定 苯肾上腺素诱导的肝细胞有丝分裂通过α-1B肾上腺素能 受体结合到tTGase G蛋白亚基Galphah，无论这是 激活MAPK通路，以及这种激活可能是通过什么机制 发生的。此外，tTGase交联活性的机制 可能影响上游事件在细胞调亡级联中也将被探索。 与健康相关：希望通过更好地了解分子 乙醇影响肝纤维化、肝细胞有丝分裂和肝纤维化的机制 细胞凋亡，可能是更有效和合理的治疗干预 发展起来的。

DESCRIPTION: This proposal is a continuation of our studies which attempt to elucidate the molecular bases of cirrhosis in alcoholic liver disease. Hepatic fibrogenes caused by alcohol abuse or other etiologies is a complex process that involves a balance between liver cell proliferation and cell death, as well as the increased deposition and modeling of extracellular matrix (ECM) proteins. Our recent studies provide evidence for the significance of one factor, tissue transglutaminase (tTG), in many of these interactions. This ubiquitous enzyme has characteristics that may induce either apoptosis or cell proliferation, and it appears to contribute to the fibrotic process in a number of ways. This proposal is an attempt to elucidate the mechanisms by which tTG affects the process of hepatic mitogenesis or apoptosis, especially as it pertains to ethanol administration. Specific Aims: 1) To determine the pathways and functional significance of alpha-1 adrenergic signaling in hepatocytes; 2) To investigate the downstream effects of alpha-1 adrenergic signaling on hepatocyte mitogenesis; and 3) To delineate the mechanisms by which tTGase cross-linking activity inhibits proliferation and enhances apoptosis in hepatocytes. These studies will entail determining whether phenylephrine-induced hepatocyte mitogenesis acts through alpha-1B adrenergic receptor binding coupled to the tTGase G-protein subunit, Galphah, whether this activates the MAPK pathway, and by what mechanism this activation may be occurring. In addition, the mechanism by which tTGase cross-linking activity may affect upstream events in the apoptosis cascade will also be explored. Health Relatedness: It is hoped that by better understanding the molecular mechanisms by which ethanol affects fibrogenesis, hepatic mitogenesis, and apoptosis, more effective and rational therapeutic intervention may be developed.