Liver fibrosis and ethanol: role of the transcription factor, Egr-1

肝纤维化和乙醇：转录因子 Egr-1 的作用

• 批准号: 7571976
• 负责人: MICHELE T PRITCHARD
• 金额: $ 10.75万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-08 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7571976
• 关键词: Acute; Acute Hepatitis; Address; Alcoholic Liver Diseases; Alcohols; Antioxidants; Attenuated; Biological; Biological Models; Biology; CCL2 gene; COL1A2 gene; CXCL2 gene; Cell Culture Techniques; Cell Cycle Progression; Cell physiology; Cells; Cellular biology; Characteristics; Chronic; Cicatrix; Cirrhosis; Clinic; Collagen; Collagen Diseases; Data; Development; Development Plans; Disease; Early Gene Transcriptions; Endothelial Cells; Endotoxemia; Environment; Ethanol; Extracellular Matrix; Fatty Liver; Fibrosis; Gene Expression; Generations; Genes; Growth; Healed; Health; Hepatic; Hepatic Stellate Cell; Hepatitis; Hepatocyte; Immediate-Early Genes; Immunology; Inflammation; Inflammatory; Injury; Injury to Liver; Institution; Intercellular adhesion molecule 1; Ischemia; Kupffer Cells; Laboratories; Lead; Lesion; Literature; Liver; Liver Failure; Liver Fibrosis; Liver diseases; Maintenance; Matrix Metalloproteinases; Mediator of activation protein; Mentors; Mentorship; Modeling; Molecular; Mus; Outcome; Pathology; Patients; Phenotype; Platelet-Derived Growth Factor; Play; Positioning Attribute; Principal Investigator; Process; Production; Productivity; Publishing; Recovery; Reperfusion Therapy; Research; Research Institute; Research Personnel; Resolution; Role; Solid; Staging; Steatohepatitis; System; TIMP1 gene; TP53 gene; Testing; Therapeutic; Training; United States; Work; Wound Healing; alcohol exposure; base; career; career development; cell type; chronic alcohol ingestion; design; feeding; healing; improved; injury and repair; liver cell proliferation; liver transplantation; mouse model; novel; professor; programs; public health relevance; response; skills training; transcription factor

DESCRIPTION (provided by applicant): The Candidate is a young investigator dedicated to developing an academic research career focused on the identification and characterization of molecular mechanisms which contribute to ethanol-induced liver injury. The candidate has a strong background in innate immunology and has developed a particular expertise in the use of different mouse models that recapitulate hepatic steatosis, hepatitis and fibrosis to test specific hypotheses involved in development of liver injury. Use of these model systems has revealed an important role for the transcription factor Egr-1 in each of these systems. The Candidate's recent and current work has provided her with the opportunity to develop her own research program and begin her transition to independence. The Career Development plan described in this application outlines 2-years of mentored training which includes technical skills training in addition to career development activities designed to promote the successful transition to independence. A 3-year program of independent scientific and career development after successful recruitment as an Assistant Professor position to a competitive academic research institution is also outlined. The Candidate's Mentor has a proven track-record of excellent scientific productivity and successful mentorship and can provide the Candidate with a solid research environment in her laboratory at the Lerner Research Institute at the Cleveland Clinic. Research plan: Ethanol-induced hepatic fibrosis is a severe form of liver disease. Although great strides have been made in understanding the mechanisms by which fibrosis is induced and how it resolves, these discoveries have not yet lead to improved therapeutic strategies. Egr-1 is a transcription factor that regulates a broad array of genes involved in inflammation and in the wound healing response. Our published studies demonstrate that Egr-1 is a critical modulator of ethanol-induced fatty liver and acute hepatic inflammation in mice. Due to the ability of Egr-1 to regulate genes that are modulators of fibrosis, we hypothesize that Egr-1 will be an important contributor to fibrotic disease in the liver. Our preliminary data reveal that, in egr-1-/- mice, CCI4- induced liver injury and fibrosis are enhanced, suggesting previously unknown, novel biological roles for Egr- 1 in fibrosis. In three specific aims, we will characterize the hepatic pathology in egr-1-/- mice after CCI4 exposure alone and in mice exposed to chronic ethanol and CCI4, focusing on the biology of hepatic stellate cells. We expect that the results from these studies will reveal previously unrecognized roles of Egr-1 in hepatic fibrosis and hepatic stellate cell biology. Public Health Relevance: Hepatic fibrosis, or scarring of the liver, is a significant health problem in the United States. Regardless of the agent responsible for hepatic fibrosis, the outcome is the same; patients with fibrotic livers are likely to progress to cirrhosis and succumb due to liver failure. Currently, liver transplantation is the only cure for end stage liver disease. Our studies will contribute to our understanding of fibrosis and help to define new ways to can heal fibrotic lesions in the liver.

描述（由申请人提供）：候选人是一名年轻的研究者，致力于发展学术研究事业，重点是鉴定和表征导致乙醇诱导肝损伤的分子机制。候选人在先天免疫学方面有很强的背景，并在使用不同的小鼠模型方面发展了特殊的专业知识，这些模型概括了肝脂肪变性，肝炎和纤维化，以测试涉及肝损伤发展的特定假设。这些模型系统的使用揭示了转录因子Egr-1在这些系统中的每一个中的重要作用。候选人最近和目前的工作为她提供了发展自己的研究计划并开始向独立过渡的机会。本申请中描述的职业发展计划概述了2年的指导培训，其中包括技术技能培训以及旨在促进成功过渡到独立的职业发展活动。还概述了在成功招聘为具有竞争力的学术研究机构的助理教授职位后，为期3年的独立科学和职业发展计划。候选人的导师具有出色的科学生产力和成功的指导的良好记录，可以在克利夫兰诊所勒纳研究所的实验室为候选人提供坚实的研究环境。研究计划：乙醇诱导的肝纤维化是一种严重的肝脏疾病。虽然在理解纤维化的诱导机制和如何解决方面取得了很大进展，但这些发现尚未导致改善的治疗策略。Egr-1是一种转录因子，调节炎症和伤口愈合反应中涉及的广泛基因。我们发表的研究表明，Egr-1是小鼠乙醇诱导的脂肪肝和急性肝脏炎症的关键调节剂。由于Egr-1能够调节作为纤维化调节剂的基因，我们假设Egr-1将是肝脏纤维化疾病的重要贡献者。我们的初步数据显示，在Egr-1-/-小鼠中，CCl 4诱导的肝损伤和纤维化增强，表明Egr- 1在纤维化中以前未知的新生物学作用。在三个具体的目标，我们将描述的肝脏病理学在CCl 4单独暴露后，并在小鼠暴露于慢性乙醇和CCl 4，专注于肝星状细胞的生物学。我们期望这些研究的结果将揭示以前未被认识的Egr-1在肝纤维化和肝星状细胞生物学中的作用。 公共卫生相关性：肝纤维化或肝脏瘢痕形成在美国是一个重要的健康问题。无论是哪种药物导致肝纤维化，结果都是一样的;肝纤维化患者可能进展为肝硬化并死于肝功能衰竭。目前，肝移植是治疗终末期肝病的唯一方法。我们的研究将有助于我们对纤维化的理解，并有助于确定治愈肝脏纤维化病变的新方法。