Molecular Regulation of Hepatocyte Proliferation and Liver Regeneration

项目摘要/摘要 我们研究的长期目标是更好地了解调节肝细胞的分子机制。 肝再生过程中的增殖。肝脏有一种先天的能力，可以在受损后自我修复， 恢复其原有的结构和功能。及时或加强肝脏修复或再生可导致恢复 而延迟或抑制肝脏修复或再生会导致肆无忌惮的伤害和死亡。 值得注意的是，肝细胞增殖是急慢性肝脏修复反应的第一线。 对人体有害，是肝脏再生的驱动力。因此，了解肝细胞复制是如何 在制定治疗肝损伤的临床策略中，调节是至关重要的。各种增长 因子和细胞因子形成复杂的调控网络，协调调节增殖反应 肝细胞的数量减少到肝脏质量的大量减少。然而，控制这一过程的精确分子机制 肝修复过程中肝细胞周期的启动、进展和终止 难以捉摸。因此，这项建议的目的是进一步了解 肝再生过程中的肝细胞复制。催乳素(PRL)受体(PRLR)信号系统是 在所有脊椎动物中高度保守，包括配体和受体结构以及下游信号 分子。PRLR信号有助于调节许多功能，特别是相关的功能 具有繁殖和哺乳功能。肝脏是PRLR表达最高的几个组织之一。 然而，目前对肝脏PRLR信号系统的功能知之甚少。我们的工作和其他人的工作都 将PRLR信号系统与肝细胞扩张的调节联系起来。根据我们的初步研究， 我们集中假设PRLR信号系统通过YES相关蛋白发挥有丝分裂信号。 (YAP)，在肝再生过程中刺激肝细胞增殖。我们将测试我们的中心假设， 因此，通过追求以下两个具体目标来实现本应用程序的目标。具体目标1： 明确肝细胞中的PRLR/YAP有丝分裂信号通路。具体目标2：确定 PRLR信号系统在肝再生过程中调节肝细胞周期中的作用。建议数 研究将使我们能够揭示PRLR信号系统是如何作为一个新的和关键的调制器发挥作用的 当被激活时，刺激肝细胞扩张，以补偿受损肝脏中丢失的肝脏质量。在……里面 此外，拟议的研究将为评估PRLR系统作为一项新的 通过促进肝细胞增殖从而促进肝脏修复来治疗肝损伤的靶点。 1

PROJECT SUMMARY/ABSTRACT The long term goal of our research is to better understand the molecular mechanisms regulating hepatocyte proliferation during liver regeneration. The liver possesses an innate capability to repair itself after damage, restoring its original structures and functions. Timely or enhanced liver repair or regeneration leads to recovery and survival, whereas delayed or inhibited liver repair or regeneration results in unrestrained injury and death. Remarkably, hepatocyte proliferation constitutes the first line of repair response to acute and chronic liver injuries and is the driving force for liver regeneration. Therefore, understanding how hepatocyte replication is regulated is of paramount importance in developing clinical strategies to treat liver injuries. Various growth factors and cytokines form complex regulatory networks and coordinately modulate the proliferative response of hepatocytes to massive liver mass loss. However, the precise molecular mechanisms that control the initiation, progression, and termination of the hepatocyte cell cycle during the course of liver repair remain elusive. Hence, the objective of this proposal is to further understand the molecular mechanisms governing hepatocyte replication during liver regeneration. The prolactin (PRL) receptor (PRLR) signaling system is highly conserved among all vertebrates, including ligand and receptor structure and downstream signaling molecules. PRLR signaling contributes to the regulation of numerous functions, especially those associated with reproduction and lactation. The liver is among several tissues with the highest PRLR expression. However, functions of hepatic PRLR signaling system are poorly understood. Our work and that of others have linked the PRLR signaling system to the regulation of hepatocyte expansion. Based on our preliminary studies, we centrally hypothesize that the PRLR signaling system exerts mitogenic signaling via yes-associated protein (YAP), stimulating hepatocyte proliferation during liver regeneration. We will test our central hypothesis and, thereby, accomplish the objective of this application by pursuing the following two specific aims. Specific Aim 1: Define the PRLR/YAP mitogenic signaling pathway in hepatocytes. Specific Aim 2: Determine the mode of action of the PRLR signaling system in regulating hepatocyte cell cycle during liver regeneration. The proposed studies will enable us to reveal how the PRLR signaling system acts as a novel and critical modulator that when activated stimulates hepatocyte expansion to compensate for lost liver mass in an injured liver. In addition, the proposed studies will provide essential information for evaluating the PRLR system as a new target for treating liver injuries through enhancing hepatocyte proliferation and thereby liver repair. 1