Estrogen Regulation of Hepatic Growth

雌激素对肝脏生长的调节

• 批准号: 8850849
• 负责人: Wolfram Goessling
• 金额: $ 34.94万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-06 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8850849
• 关键词: Adult; Affect; Apoptosis; Applications Grants; Cancer Model; Cell Cycle; Cell Proliferation; Cells; Chemical Models; Chemicals; Clinical; Critical Pathways; Data; Development; Embryonic Development; Endoderm; Environmental Impact; Estrogens; Etiology; Exposure to; Gene Expression Regulation; Genes; Genetic; Genetic Screening; Goals; Growth; Growth and Development function; Hematopoiesis; Hepatic; Hepatobiliary; Hepatocarcinogenesis; Hepatocyte; Homeostasis; Incidence; Injury; Lead; Liver; Liver Dysfunction; Liver diseases; Liver neoplasms; Malignant Neoplasms; Malignant neoplasm of liver; Mechanics; Mediating; Metabolic; Methodology; Modeling; Modification; Molecular; Morbidity - disease rate; Natural regeneration; Organ; Organism; Organogenesis; Outcome; Patients; Phase; Phase I Clinical Trials; Plants; Pregnancy; Recommendation; Recovery; Regulation; Reporter; Role; Screening Result; Signal Pathway; Signal Transduction; Source; Structure; Surgical Models; System; Time; Tissues; Toxin; Transgenic Organisms; United States; Work; Zebrafish; cancer therapy; carcinogenesis; cell type; cellular targeting; chemical genetics; chronic liver disease; clinically relevant; early childhood; estrogenic activity; in vivo; knock-down; liver cancer prevention; liver function; liver injury; malformation; mortality; mutant; novel therapeutics; nutrition; organ regeneration; repaired; reproductive; reproductive function; response; screening; therapeutic target; tumor; tumor progression; xenoestrogen

DESCRIPTION (provided by applicant): Liver disease is a common cause of morbidity and mortality in the United States; approximately 400,000 patients suffer from chronic liver disease, caused by a variety of etiologies, and the incidence is rising. More than 25,000 patients die each year from complications of liver dysfunction, 1700 alone while awaiting liver trans- plant. Perturbations of liver growth can cause hepatic neoplasia. In addition, as the primary metabolic organ, the liver is exposed to both environmental and endogenous toxins, necessitating ongoing repair and regeneration. Using the zebrafish (Danio rerio) model, we have successfully elucidated a highly specific regulatory role for Wnt signaling in both liver development and regeneration, conserved across vertebrate species, and established a model to discover novel therapeutics for toxic liver injury. We recently completed a chemical genetic screen to identify regulators of liver development in zebrafish; we have successfully used this approach previously to elucidate conserved modifiers of hematopoiesis, one of which is currently in a phase I clinical trial. Through this screening methodology, we have discovered that estrogen is an important modifier of liver specification and growth. Estrogen is a well-characterized transcriptional regulator, which is frequently associated with cancer progression and may correspond with response to therapy. Furthermore, xenoestrogens, both naturally occurring and manufactured compounds that mimic the action of estrogen in the cell, have been shown to modulate the development and function of reproductive organs, as well as contribute to both cancer formation and therapy. Our long-term goal is to understand the molecular and cellular mechanisms by which estrogenic compounds affect the liver. Our objective here is to characterize the functional implications of estrogen exposure on liver growth during development, in regeneration after injury, and in carcinogenesis. Our central hypothesis is that estrogen exerts time and cell-type specific effects on the liver through interaction with other signaling pathways, particularly Wnt signaling. This hypothesis has been derived from our own screening results and subsequent preliminary data as well as clinical observations and cancer studies. The rationale for our work is that a detailed understanding of the impact of estrogen on liver growth will enable recommendations regarding nutrition and exposure during pregnancy and in early childhood, and reveal potential new targets for liver cancer prevention and treatment. In Specific Aim 1, we seek to define the role, timing, and targets of estrogen signaling during endoderm specification and liver formation; these studies will make use of both chemical and genetic modification of estrogen levels and signaling over the course of development, and utilize an extensive array of phenotypic, histological and functional methodologies. In Specific Aim 2, we will investigate whether estrogenic activity has an impact on organ regeneration and cancer growth; we will use previously devised surgical and chemical models of liver injury and a zebrafish liver cancer model to examine the effect of estrogen modulation on the recovery or destruction of hepatic structure and function.

描述（由申请人提供）：肝病是美国发病和死亡率的常见原因；大约40万例患者患有慢性肝病，这是由于多种病因引起的，并且发生率正在上升。每年有25,000多名患者死于肝功能障碍的并发症，仅1700例，同时等待肝脏植物。肝脏生长的扰动会导致肝肿瘤。此外，作为主要的代谢器官，肝脏会暴露于环境和内源性毒素中，因此需要持续维修和再生。使用斑马鱼（Danio Rerio）模型，我们成功地阐明了Wnt信号在肝发育和再生中的高度特异性调节作用，在脊椎动物中保守，并建立了一种模型，以发现针对有毒肝损伤的新型治疗方法。我们最近完成了一个化学遗传筛选，以识别斑马鱼肝发育的调节剂。我们以前已经成功地使用了这种方法来阐明造血的保守修饰剂，其中一种目前正在I期临床试验中。通过这种筛查方法，我们发现雌激素是肝脏规范和生长的重要修饰符。雌激素是一种特征良好的转录调节剂，经常与癌症进展有关，并且可能与对治疗的反应相对应。此外，已经证明异雌激素是天然发生的和生产的化合物，这些化合物模仿了雌激素在细胞中的作用，可以调节生殖器官的发育和功能，并促进癌症形成和治疗。我们的长期目标是了解雌激素化合物影响肝脏的分子和细胞机制。我们的目的是表征雌激素暴露对发育过程中肝脏生长，损伤后再生和致癌作用的功能意义。我们的中心假设是，雌激素通过与其他信号通路（尤其是Wnt信号传导）的相互作用来对肝脏发挥时间和细胞类型的特异性影响。该假设是从我们自己的筛查结果以及随后的初步数据以及临床观察和癌症研究中得出的。我们工作的理由是，对雌激素对肝脏生长的影响的详细理解将使有关怀孕期间和幼儿期间的营养和暴露的建议，并揭示了预防肝癌预防和治疗的潜在新目标。在特定的目标1中，我们试图在内胚层规范和肝脏形成期间定义雌激素信号的作用，时机和靶标。这些研究将利用雌激素水平的化学和遗传修饰以及在发育过程中的信号传导，并利用各种表型，组织学和功能方法。在特定目标2中，我们将研究雌激素活性是否对器官再生和癌症生长有影响。我们将使用先前设计的肝损伤手术和化学模型和斑马鱼肝癌模型来检查雌激素调节对肝结构和功能的恢复或破坏的影响。