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

描述(由申请人提供)：应聘者是一名年轻的研究人员，致力于发展学术研究生涯，专注于识别和表征导致乙醇诱导的肝损伤的分子机制。应聘者在先天性免疫学方面有很强的背景，在使用不同的小鼠模型来测试涉及肝脏损伤发展的特定假说方面具有特殊的专业知识。这些模型系统的使用揭示了转录因子Egr-1在每个系统中的重要作用。这位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。本申请书中描述的职业发展计划概述了为期两年的有指导的培训，其中除了旨在促进成功过渡到独立的职业发展活动外，还包括技术技能培训。此外，还概述了在一家有竞争力的学术研究机构成功招聘助理教授职位后，一个为期3年的自主科研和职业发展计划。候选人的导师拥有卓越的科学生产力和成功的指导记录，可以为候选人在克利夫兰诊所勒纳研究所的实验室提供坚实的研究环境。研究计划：酒精性肝纤维化是一种严重的肝病。虽然在了解纤维化的机制和如何解决方面已经取得了很大的进步，但这些发现还没有带来改进的治疗策略。EGR-1是一种转录因子，调节一系列参与炎症和伤口愈合反应的基因。我们已发表的研究表明，Egr-1是乙醇诱导的小鼠脂肪肝和急性肝脏炎症的关键调节因子。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，CCI4诱导的肝损伤和纤维化得到加强，这表明先前未知的Egr-1在纤维化中发挥了新的生物学作用。在三个特定的目标中，我们将描述单独接触CCI4后EGR-1/-小鼠以及长期接触乙醇和CCI4的小鼠的肝脏病理特征，重点是肝星状细胞的生物学。我们期望这些研究的结果将揭示先前未知的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：在美国，肝纤维化或肝脏瘢痕形成是一个重大的健康问题。不管是哪种因素导致肝纤维化，结果都是一样的；肝纤维化患者很可能进展为肝硬变，并因肝功能衰竭而死亡。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，并有助于定义治疗肝脏纤维化病变的新方法。

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.