Estrogen Regulation of Hepatic Growth

雌激素对肝脏生长的调节

• 批准号: 8187518
• 负责人: Wolfram Goessling
• 金额: $ 40.12万
• 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/8187518
• 关键词: Adult; Affect; Apoptosis; Applications Grants; Cancer Model; Cell Cycle; Cell Proliferation; Cells; Chemical Models; Chemicals; Chronic; 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; Screening procedure; 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; clinically relevant; early childhood; estrogenic activity; in vivo; knock-down; liver cancer prevention; liver function; malformation; mortality; mutant; novel therapeutics; nutrition; organ regeneration; repaired; reproductive; reproductive function; response; 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. PUBLIC HEALTH RELEVANCE: In this grant application, we plan to study the role of estrogen modulation from both endogenous and environmental sources in liver development, regeneration and cancer formation. We identified estrogen as a potent regulator of liver formation through a chemical genetic screen in the zebrafish. Our findings will have important clinical relevance for intrauterine and early childhood exposure to estrogenic substances, and may elucidate possible therapeutic targets to enhance recovery from liver injury and treat liver cancer.

描述（由申请人提供）：肝病是美国发病和死亡的常见原因；大约有40万名患者患有由多种病因引起的慢性肝病，并且发病率正在上升。每年有超过 25,000 名患者死于肝功能障碍并发症，其中 1700 名患者在等待肝移植期间死亡。肝脏生长的干扰可导致肝肿瘤。此外，作为主要的代谢器官，肝脏暴露于环境和内源性毒素，需要持续修复和再生。使用斑马鱼（斑马鱼）模型，我们成功阐明了 Wnt 信号在肝脏发育和再生中的高度特异性调节作用，该作用在脊椎动物物种中保守，并建立了一个模型来发现中毒性肝损伤的新疗法。我们最近完成了一项化学遗传筛选，以确定斑马鱼肝脏发育的调节因子；我们之前已经成功地使用这种方法来阐明造血作用的保守修饰因子，其中之一目前正处于 I 期临床试验中。通过这种筛选方法，我们发现雌激素是肝脏规格和生长的重要调节剂。雌激素是一种特征明确的转录调节因子，通常与癌症进展相关，并且可能与治疗反应相对应。此外，异种雌激素，无论是天然存在的还是人造的模仿细胞中雌激素作用的化合物，已被证明可以调节生殖器官的发育和功能，并有助于癌症的形成和治疗。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。我们的目标是描述雌激素暴露对发育过程中肝脏生长、损伤后再生和癌变过程中的功能影响。我们的中心假设是，雌激素通过与其他信号通路（特别是 Wnt 信号通路）相互作用，对肝脏产生时间和细胞类型的特异性影响。这一假设源自我们自己的筛查结果和随后的初步数据以及临床观察和癌症研究。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有助于就怀孕期间和幼儿期的营养和暴露提出建议，并揭示肝癌预防和治疗的潜在新目标。在具体目标 1 中，我们试图定义在内胚层规范和肝脏形成过程中雌激素信号传导的作用、时间和目标；这些研究将在发育过程中利用雌激素水平和信号传导的化学和遗传修饰，并利用广泛的表型、组织学和功能方法。在具体目标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的外科和化学模型以及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。 公共健康相关性：在这项拨款申请中，我们计划研究内源性和环境来源的雌激素调节在肝脏发育、再生和癌症形成中的作用。我们通过斑马鱼的化学遗传筛选发现雌激素是肝脏形成的有效调节剂。我们的研究结果对于子宫内和儿童早期接触雌激素物质具有重要的临床意义，并可能阐明可能的治疗靶点，以促进肝损伤的恢复和治疗肝癌。