Estrogen Regulation of Hepatic Growth

描述(申请人提供)：在美国，肝病是导致发病率和死亡率的常见原因；大约有40万名患者患有由各种原因引起的慢性肝病，而且发病率还在上升。每年有超过25000名患者死于肝功能障碍的并发症，仅在等待肝脏移植期间就有1700人死亡。肝脏生长的紊乱会导致肝脏肿瘤。此外，作为主要的代谢器官，肝脏暴露在环境和内源性毒素中，需要持续的修复和再生。利用斑马鱼(Danio Rerio)的模型，我们成功地阐明了Wnt信号在肝脏发育和再生中的高度特异性调节作用，并在脊椎动物中保守，并建立了一个模型，以发现治疗中毒性肝损伤的新疗法。我们最近完成了一项化学基因筛查，以确定斑马鱼肝脏发育的调控因素；我们之前曾成功使用这一方法来阐明保守的造血修饰物，其中一项目前正处于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。雌激素是一种转录调节因子，常与癌症进展相关，并可能与治疗反应相对应。此外，异种雌激素，既有天然存在的化合物，也有模拟雌激素在细胞中的作用的人造化合物，已被证明可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肝脏发育、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信号通路的相互作用，对肝脏施加时间和细胞类型的特异性影响。这一假设是从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中得出的。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使人们能够就孕期和儿童早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靶点。在具体目标1中，我们试图确定雌激素信号在内胚层指定和肝脏形成过程中的作用、时机和靶点；这些研究将利用化学和遗传修饰雌激素水平和发育过程中的信号，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影响器官再生和肿瘤生长；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研究雌激素调节对肝脏结构和功能恢复或破坏的影响。

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.