BASES OF CIRRHOSIS IN ALCOHOLIC LIVER DISEASE

酒精性肝病中肝硬化的基础

• 批准号: 3109546
• 负责人: MARK ALLEN ZERN
• 金额: $ 30.93万
• 依托单位: ROGER WILLIAMS HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-09-01 至 1991-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3109546
• 关键词: Cercopithecidae; albumins; alcoholic liver cirrhosis; alcoholism /alcohol abuse; biopsy; cell free system; chronic disease /disorder; collagen; corticosteroids; disease /disorder proneness /risk; electron microscopy; extracellular matrix proteins; fatty liver; fibrogenesis; fibronectins; genetic transcription; human subject; human tissue; interferons; laboratory rat; liver cells; liver disorder diagnosis; liver failure; liver metabolism; messenger RNA; molecular pathology; noninvasive diagnosis; nuclear runoff assay; nucleic acid hybridization; nucleic acid probes; nucleic acid sequence; procollagen; prognosis; protein biosynthesis; radioimmunoassay; restriction fragment length polymorphism; tissue /cell culture; transforming growth factors; tumor necrosis factor alpha

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.

这一建议是对我们 最初的目标是试图了解分子 负责肝纤维化的机制。 我们定义 可能引发纤维化事件的特定因素， 可以改善病情，一个测试，可以诊断谁 通过更好地理解 影响纤维化过程的元素，它变得 可以设计合理的治疗干预。 具体 目的：1）鉴定负责合成 肝脏中的胶原蛋白。 2)为了确定两种细胞因子，肿瘤 坏死因子（TNF）和转化生长因子β （TGF-β）启动并促进纤维化过程。 3)到 描述γ-干扰素的抗纤维化作用， 皮质类固醇 4)为了确定I型糖尿病的遗传变异 胶原蛋白基因可能与 酒精性肝硬化 方法：1）前胶原mRNA 通过原位杂交定位在特定细胞中。 2)的影响 TNF和TGF-β对基质蛋白合成的影响将在 在肝硬化动物模型中，通过北方 杂交分析、核连续分析和原位杂交分析， 杂交方法 3)将用以下药物处理细胞和动物： γ-干扰素的抗纤维化的基础 方面的影响. 瞬时表达载体系统将用于 确定地塞米松抑制胶原蛋白的机制 合成. 4)限制性片段长度分析 胶原基因的多态性将在 大家庭的酗酒者，以确定遗传基础， 肝硬化 健康相关性：通过实现这一目标 建议我们将制定一个一般模型的发病机制 酒精性肝病的治疗和治疗辅助剂的制定 疗法 确定一个与一个明显相关的单倍型， 特定的酗酒者发展成肝硬化的倾向将 建立临床相关测试。 定义抗纤维化 皮质类固醇和γ-干扰素的作用可能有助于 确定哪些慢性肝病患者会成功 这些治疗药物的干预。