BASES OF CIRRHOSIS IN ALCOHOLIC LIVER DISEASE
酒精性肝病中肝硬化的基础
基本信息
- 批准号:6629551
- 负责人:
- 金额:$ 34.31万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:1988
- 资助国家:美国
- 起止时间:1988-09-01 至 2006-03-31
- 项目状态:已结题
- 来源:
- 关键词:alcoholic liver cirrhosis alcoholism /alcohol abuse alpha adrenergic receptor apoptosis cell proliferation enzyme activity ethanol extracellular matrix proteins guanosinetriphosphatases hormone regulation /control mechanism laboratory rat liver cells liver pharmacology phenylephrine protein glutamine gamma glutamyltransferase somatotropin tissue /cell culture
项目摘要
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.
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
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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