BASES OF CIRRHOSIS IN ALCOHOLIC LIVER DISEASE

描述：本建议是我们研究的继续， 阐明酒精性肝病肝硬化的分子基础。肝 由酒精滥用或其他病因引起的纤维化是一个复杂的过程， 这涉及肝细胞增殖和细胞死亡之间的平衡， 以及细胞外基质（ECM）的沉积和建模增加 proteins.我们最近的研究提供了证据， 在许多这些相互作用中，组织转氨酶（tTG）是一个重要的因子。这 普遍存在的酶具有可诱导细胞凋亡或细胞凋亡的特性， 增殖，它似乎有助于纤维化过程中的一些 的方式。这一提议试图阐明tTG 影响肝细胞有丝分裂或凋亡的过程，特别是当它 涉及乙醇给药。具体目标：1）确定途径 和肝细胞中α-1肾上腺素能信号传导的功能意义; 2） 为了研究α-1肾上腺素能信号传导的下游作用， 肝细胞有丝分裂;和3）描述tTGase 交联活性抑制细胞增殖并增强细胞凋亡， 肝细胞这些研究将需要确定是否 苯肾上腺素诱导的肝细胞有丝分裂通过α-1B肾上腺素能受体发挥作用 受体结合偶联到tTGase G蛋白亚基，Galphah，无论这是否 激活MAPK通路，以及这种激活可能是通过什么机制 正在发生。此外，tTGase交联活性的机制 可能影响上游事件的细胞凋亡级联反应也将进行探讨。 健康相关性：希望通过更好地了解分子 乙醇影响纤维形成、肝有丝分裂和 凋亡，更有效和合理的治疗干预， 开发

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.