BASES OF CIRRHOSIS IN ALCOHOLIC LIVER DISEASE

这项提议代表着我们对我们的 最初的目标是试图理解分子 肝纤维化的发生机制。我们正在定义 可能引发纤维化事件的特定因素，即 可以改善病情，以及可以诊断谁是 把它开发出来。通过更好地了解 影响纤维化过程的因素，它就会变成 为设计合理的治疗干预措施提供可能。特定的 目的：1)确定负责合成的细胞(S) 肝脏中的胶原蛋白。2)确定两种细胞因子、肿瘤 肿瘤坏死因子和转化生长因子β (转化生长因子-β)启动和促进纤维化过程。3)至 阐明干扰素和干扰素的抗纤维化作用 皮质类固醇。4)确定I型的遗传变异如何 胶原蛋白基因可能与糖尿病的发生发展有关 酒精性肝硬变。方法：1)将前胶原mRNA 通过原位杂交定位于特定细胞。2)网络的影响 将于#年研究肿瘤坏死因子和转化生长因子-β对基质蛋白合成的影响。 培养细胞及Northern在肝硬变动物模型中的应用 杂交分析、核连续分析和原位分析 杂交。3)细胞和肝硬变动物将接受 γ-干扰素阐明其抗纤维化作用的基础 效果。将使用瞬时表达载体系统来 明确地塞米松抑制胶原蛋白的机制 综合。4)限制性片段长度分析 一种胶原基因的多态性将在一种 扩大酗酒者家族以确定其遗传基础 肝硬变。与健康相关：通过实现这一目标 建议我们将制定一个发病机制的通用模型 酒精性肝病的治疗和辅助治疗 心理治疗。明确与单倍型相关的单倍型的鉴定 某一特定酗酒者患上肝硬变的倾向将 建立一个与临床相关的测试。定义抗纤维化药物 皮质类固醇和γ-干扰素的作用可能会有所帮助 确定哪些慢性肝病患者将获得成功 使用这些治疗剂中的一种进行干预。

This proposal represents a continuation and expansion of our initial objective of attempting to understand the molecular mechanisms responsible for hepatic fibrogenesis. We are defining specific factors that may initiate the fibrotic events, agents that may ameliorate the condition, and a test that may diagnose who develops it. By better understanding the interaction of the elements that influence the fibrogenic process, it becomes possible to design rational therapeutic intervention. Specific Aims: 1) To identify the cell(s) responsible for the synthesis of collagen in the liver. 2) To determine how two cytokines, tumor necrosis factor (TNF) and transformation growth factor beta (TGF-beta) initiate and promote the fibrogenic process. 3) To delineate the antifibrogenic effects of gamma-interferon and corticosteroids. 4) To establish how genetic variation in a type I collagen gene may be associated with the development of alcoholic cirrhosis. Methods: 1) Procollagen mRNA will be located in specific cells by in situ hybridization. 2) The effects of TNF and TGF-beta on matrix protein synthesis will be studied in cultured cells and in animal models of cirrhosis by Northern hybridization analysis, nuclear run-on assays, and in situ hybridization. 3) Cells and cirrhotic animals will be treated with gamma-interferon to delineate the basis of its anti-fibrogenic effects. A transients expression vector system will be used to define the mechanisms by which dexamethasone inhibits collagen synthesis. 4) Analysis of restriction fragment length polymorphisms of a collagen gene will be undertaken in an extended family of alcoholics to define a genetic basis for cirrhosis. Health relatedness: By accomplishing the aims of this proposal we will formulate a general model for the pathogenesis of alcoholic liver disease and therapy aid in the formulation of therapy. Identification of a haplotype clearly associated with a propensity for a specific alcoholic to develop cirrhosis will establish a clinically relevant test. Defining the antifibrogenic actions of corticosteroids and gamma-interferon may help determine which patients with chronic liver disease will prosper from intervention with one of these therapeutic agents.