PGE2 and wnt signaling during zebrafish liver development and regeneration

描述(由申请人提供)： 在美国，肝病是发病率和死亡率的常见原因。描述参与肝脏发育的关键途径对于我们了解正常的肝功能和维持组织内环境平衡是必不可少的。肝脏发育障碍可导致肝胆系统严重畸形和肝脏肿瘤。此外，肝脏暴露在环境和内源性毒素中，需要持续的修复和再生。WNT信号影响几个内胚层器官的细胞增殖和分化，以及成人正在进行的修复。利用斑马鱼(Danio Rerio)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。我们进一步发现，WNT活性增强对损伤后器官再生的积极影响在脊椎动物物种中是保守的。此外，利用斑马鱼，我们询问了WNT活性的保守修饰物在体内的功能需求。然而，Wnt信号通路与肝脏形成、功能和再生的其他关键调节因子之间的复杂相互作用在很大程度上仍不清楚。在这里，我计划扩展我最初的K08研究，以表征WNT活性的临床相关修饰物PGE2的功能关系。在第一个具体目标中，我试图确定PGE2影响WNT介导的肝脏规范和生长的机制。在第二个特定目标中，我将研究PGE2和WNT信号通路在损伤后肝再生中的协同调节作用。这些研究将有助于深入了解肝脏分化和生长的基本机制，并将有助于确定潜在的治疗靶点，以改善肝脏再生和癌症治疗。通过R03小额赠款计划提供资金将是完成本提案中概述的工作的关键；除了支付技术援助的费用外，赠款资金将用于直接资助那些本来可能过于昂贵的实验，因为我已经开始向独立调查员过渡。 公共卫生相关性： 在美国，肝病是一种常见的疾病和死亡原因。代谢紊乱、肝硬变、病毒感染、药物过量和癌变都可能导致肝功能衰竭，需要手术切除或移植。这项研究试图找出调节肝脏规格和生长的因素，作为新的治疗策略的合理靶点，以促进肝脏再生或抑制癌症进展。

DESCRIPTION (provided by applicant): Liver disease is a common cause of morbidity and mortality in the United States. Delineating the critical pathways involved in liver development is essential for our knowledge of normal liver function and the maintenance of tissue homeostasis. Disturbances in liver development can lead to severe malformations of the hepatobiliary system and hepatic neoplasia. Additionally, the liver is exposed to both environmental and endogenous toxins, necessitating ongoing repair and regeneration. Wnt signaling influences cellular proliferation and differentiation in several endodermal organs as well as ongoing repair in the adult. Using the zebrafish (Danio rerio) model, we have successfully elucidated a highly specific regulatory role for wnt signaling in both liver development and regeneration. We have further discovered that the positive effect of enhanced wnt activity on organ regeneration following injury is conserved across vertebrate species. Additionally, using zebrafish, we interrogated the functional requirement of conserved modifiers of wnt activity in vivo. The complex interactions between the Wnt signaling pathway and other critical regulators of liver formation, function and regeneration, however, remain largely undefined. Here, I plan extend my original K08 investigation to characterize the functional relationship to a clinically relevant modifier of wnt activity, PGE2. In the first Specific Aim, I seek to determine the mechanism by which PGE2 influences wnt-mediated liver specification and growth. In the second Specific Aim, I will investigate the coordinate regulatory effects of PGE2 and the wnt signaling pathway on liver regeneration following injury. These studies will provide insight into the basic mechanisms of liver differentiation and growth, and will help to identify potential therapeutic targets to improve liver regeneration and cancer therapy. Funding through the R03 Small Grants Program will be essential to the completion of the work outlined in this proposal; in addition to defraying the cost of technical assistance, grant money will be utilized to directly fund experiments that might otherwise be too costly to conduct now that I have begun the transition to becoming an independent investigator. PUBLIC HEALTH RELEVANCE: Liver disease is a common cause of illness and death in the United States. Metabolic disturbances, cirrhosis, viral infection, drug overdose and carcinogenesis can all lead to liver failure and the need for surgical resection or transplantation. This study seeks to identify factors regulating liver specification and growth that can be utilized as rational targets for novel therapeutic strategies to facilitate liver regeneration or inhibit cancer progression.