Role of Monocyte Chemoattractant Protein (MCP)-1 in Liver Regeneration

描述（由申请方提供）：不完全肝再生是肝病恢复的障碍，也是通过活体肝移植接受移植物的患者的障碍。对调节肝再生的机制的更好理解将促进新策略的发展，以改善肝脏疾病的恢复和移植后的生存。本研究的目的是探讨单核细胞趋化蛋白（MCP）-1调控肝再生的机制。MCP-1是C-C趋化因子家族中的小的分泌蛋白。在肝脏中，枯否细胞、肝星状细胞和肝窦内皮细胞产生MCP-1，MCP-1通过自分泌和旁分泌途径发挥作用，以促进非实质细胞的趋化性和/或活化。研究表明，表达高水平MCP-1的患者更容易发生肝脏炎症和纤维化，但对MCP-1在肝再生过程中的作用知之甚少。使用小鼠模型系统的肝再生诱导的70%部分肝切除术，我们最近作出了新的发现，肝再生受损的MCP-1的情况下。我们假设MCP-1是刺激非实质细胞产生细胞因子和生长因子，促进肝细胞再生过程中的增殖所必需的。这些可溶性介质包括肿瘤坏死因子（TNF）-α？和白细胞介素（IL）-6，其由枯否细胞产生，以及肝细胞生长因子（HGF），其主要由星状细胞产生。另一个重要的介质是血管内皮生长因子（VEGF），其诱导窦状内皮细胞的增殖并且还刺激星状细胞产生HGF。本研究的具体目的是：1）确定MCP-1是否是产生枯否细胞衍生的TNF？和IL-6; 2）鉴定MCP-1如何在再生期间促进星状细胞活化和HGF产生;和3）表征MCP-1如何在再生期间调节VEGF产生和VEGF受体信号传导。为了测试每个目标，将野生型和MCP-1敲除小鼠麻醉，进行手术，并在手术后的相关时间实施安乐死。将比较野生型和MCP-1基因敲除小鼠之间的数据，以确定MCP-1如何促进非实质细胞的活化以及随后调节肝再生的可溶性介质的产生。 公共卫生相关性：这项工作可能建立单核细胞趋化蛋白（MCP）-1在调节肝再生中的重要作用。该项目的结果可以为开发新的策略提供理论基础，以促进肝脏疾病和移植手术恢复期间的MCP-1信号传导。最后，这个项目为博伊西州立大学的本科生提供了一个机会，让他们参与生物医学研究，并了解管理再生的复杂调控机制。

DESCRIPTION (provided by the applicant): Incomplete liver regeneration is an obstacle to recovery from liver disease and for patients who receive grafts through living-donor liver transplantation. Improved understanding of the mechanisms that regulate liver regeneration will facilitate the development of new strategies to improve recovery from liver disease and survival after transplantation. The purpose of this study is to investigate the mechanisms by which monocyte chemoattractant protein (MCP)-1 regulates liver regeneration. MCP-1 is a small, secreted protein in the family of C-C chemokines. In the liver, Kupffer cells, hepatic stellate cells, and sinusoidal endothelial cells produce MCP-1, which functions through autocrine and paracrine pathways to promote chemotaxis and/or activation of nonparenchymal cells. Research shows that patients who express high levels of MCP-1 are more prone to hepatic inflammation and fibrosis, but little is known about the role of MCP-1 during liver regeneration. Using a mouse model system of liver regeneration induced by 70% partial hepatectomy, we recently made the novel discovery that liver regeneration is impaired in the absence of MCP-1. We hypothesize that MCP-1 is required to stimulate nonparenchymal cells to produce the cytokines and growth factors that promote hepatocyte proliferation during regeneration. Such soluble mediators include tumor necrosis factor (TNF)-??and interleukin (IL)-6, which are produced by Kupffer cells, and hepatocyte growth factor (HGF), which is produced primarily by stellate cells. Another important mediator is vascular endothelial growth factor (VEGF), which induces the proliferation of sinusoidal endothelial cells and also stimulates stellate cells to produce HGF. The specific aims of this study are 1) to determine if MCP-1 is required for the production of Kupffer cell-derived TNF??and IL-6 during regeneration; 2) to identify how MCP-1 contributes to stellate cell activation and HGF production during regeneration; and 3) to characterize how MCP-1 modulates VEGF production and VEGF receptor signaling during regeneration. To test each aim, wild type and MCP-1 knockout mice will be anesthetized, subjected to surgery, and euthanized at relevant times after surgery. Data will be compared between wild type and MCP-1 knockout mice to determine how MCP-1 contributes to the activation of nonparenchymal cells and the subsequent production of soluble mediators that regulate liver regeneration. PUBLIC HEALTH RELEVANCE: The proposed work could establish an important role for monocyte chemoattractant protein (MCP)-1 in regulating liver regeneration. Results from this project could provide the rationale for developing new strategies to promote MCP-1 signaling during recovery from liver disease and transplantation procedures. Finally, this project provides an opportunity for undergraduates at Boise State University to participate in biomedical research and gain an appreciation of the complex regulatory mechanisms that govern regeneration.