Estrogen Regulation of Hepatic Growth

 描述（由申请人提供）：肝病是美国发病率和死亡率上升的常见原因：约400，000例患者患有慢性肝病。每年有超过25,000名患者死于终末期肝病的并发症，其中包括1700名在等待肝移植时死亡，这表明需要更好地了解疾病发病机制和改进治疗方法。肝损伤和肝癌风险患者的临床结局高度依赖于性别，外部风险因素无法完全解释。这些临床观察结果强烈表明性激素在肝病发病机制中的影响。使用斑马鱼（Danio rerio）模型，我们已经成功地阐明了核激素和G蛋白偶联受体信号传导在肝脏发育和再生中的调节作用，这些作用在脊椎动物物种中是保守的，并确定了治疗毒性肝损伤的化合物。我们还发现了雌激素信号在血管和干细胞形成中的重要作用。在过去的资助期间，我们已经确定了雌激素在发育过程中的两个不同作用，通过核激素受体esr 2抑制肝祖细胞分化为肝细胞，并通过G蛋白偶联雌激素受体gper 1促进肝细胞生长，表明雌激素是肝脏特异性和生长的重要调节剂。我们的初步研究还表明，雌激素影响肝再生和癌症形成，与肝损伤后观察到的性别差异和肝癌发病率的已发表数据一致。我们的长期目标是了解雌激素及其下游信号影响肝脏的分子和细胞机制。我们的目标是描述雌激素信号在肝脏发育、再生和癌变过程中对肝脏生长的作用。我们的中心假设是雌激素通过核激素受体和G蛋白偶联雌激素受体GPER 1作用于不同的细胞群，影响肝分化和生长的各个方面。这一假设来源于我们在前一个资助期的工作以及观察到的肝再生和癌症临床结果的性二态性。我们工作的基本原理是，详细了解雌激素对肝脏生长的影响将解释观察到的性别差异，并揭示肝癌治疗的新靶点。在具体目标1中，我们试图通过雌激素信号的化学和遗传修饰以及广泛的表型，组织学和功能分析来确定肝脏形成和生长过程中雌激素信号的细胞和分子机制。在具体目标2中，我们将研究雌激素和GPER 1通过PI 3 K/AKT/MTOR在肝再生和癌症中的作用，使用肝损伤和致癌的创新模型。我们的研究结果将揭示新的治疗靶点，以在体外扩增肝细胞数量，增强肝再生，并预防肝硬化患者的癌症形成或进展。

 DESCRIPTION (provided by applicant): Liver disease is a common cause of rising morbidity and mortality in the United States: approximately 400,000 patients suffer from chronic liver disease. More than 25,000 patients die each year from complications of end- stage liver disease, including 1700 while awaiting liver transplant, indicating the need for a better understanding of disease pathogenesis and improved therapies. Clinical outcomes in patients with liver injury and risk for liver cancer are highly gender-dependent and not fully explained by external risk factors. These clinical observations strongly suggest an impact of sex hormones in liver disease pathogenesis. Using the zebrafish (Danio rerio) model, we have successfully elucidated regulatory roles for both nuclear hormone and G protein-coupled receptor signaling in liver development and regeneration, conserved across vertebrate species, and identified compounds to treat toxic liver injury. We have also discovered in important role for estrogen signaling in blood vessel and stem cell formation. Over the last funding period, we have defined two distinct roles for estrogen during development, inhibiting hepatic progenitor differentiation into hepatocytes via nuclear hormone receptor esr2, and promoting hepatocyte growth via G protein-coupled estrogen receptor gper1, demonstrating that estrogen is an important modifier of liver specification and growth. Our Preliminary Studies also demonstrate that estrogen affects hepatic regeneration and cancer formation, consistent with the published data on the gender differences observed after liver injury and with liver cancer incidence. Our long-term goal is to understand the molecular and cellular mechanisms by which estrogen and its downstream signals affect the liver. Our objective here is to characterize the functional implications of estrogen signaling on liver growth during development, regeneration, and carcinogenesis. Our central hypothesis is that estrogen acts on different cell populations via nuclear hormone receptors and the G protein-coupled estrogen receptor GPER1 to affect diverse aspects of hepatic differentiation and growth. This hypothesis is derived from our work over the previous funding period and the observed sexual dimorphisms in clinical outcome for liver regeneration and cancer. The rationale for our work is that a detailed understanding of the impact of estrogen on liver growth will explain observed gender differences and reveal new targets for liver cancer treatment. In Specific Aim 1, we seek to define the cellular and molecular mechanisms of estrogen signaling during liver formation and growth through chemical and genetic modification of estrogen signaling and extensive phenotypic, histological and functional analysis. In Specific Aim 2, we will investigate the role of estrogen and GPER1 acting via PI3K/AKT/MTOR in liver regeneration and cancer, using innovative models of liver injury and carcinogenesis. Our results will reveal novel therapeutic targets to amplify liver cell number in vitro, enhance liver regeneration, and prevent cancer formation or progression in patients with cirrhosis.