老年肝脏肝窦内皮细胞VEGFR2及其靶基因表达异常对肝脏再生的影响机制研究

Liver of the older individual show a delayed and/or reduced proliferation after loss of mass from surgical or chemical injury. Liver sinusoidal endothelial cells(LSECs) play a key role in the initiating and neoangiogenesis in the liver regeneration. Clinical and experimental studies show that the liver regeneration capacity after liver resection in the old patients is compromised. The structural and functional abnormity of the aged LSECs might be one of the main causes of the impaired liver regeneration in the elderly. However, the cellular and molecular mechanisms that compromise the liver regeneration in the elderly is still obscure. This study will based on in vitro co-culture of the LSECs and hepatocyte, the models of rats liver resection and partial liver transplantation. The structural and functional changes of LSECs in the the aged, and their effects on the liver regneration will be investigated in the reseach. The investigation include, The role of abnormal expressions of vascular endothelial growth factor receptor 2(VEGFR2) and its target genes of the LSECs, interactions of cytokines in the aged liver regeneration. Endothelial progenior cells(EPCs) derived from the rats bone marrow would be transfused into the animal models to ameliorate the compromised liver regeneration in the old animals by repairing the injuried LSECs; The cellular and molecular mechanisms of the diminished hepatic rengeneration in the elderly and the potential theraputic methods will be explored. This research will provid us a better understanding of cellular and molecular mechanisms that contribute to the diminished hepatic regeneration rate in old-animal models and elderly humans. This study will open new doors for developing innovative strategies to ameliorate liver regeneration in the aging population after the surgery and transplantation.New therapeutic agents that target at LSECs will provide a theraputic choice to the clinical relevance of impairment of age-related liver regeneration.

肝窦内皮细胞（LSECs）在肝脏再生的启动和新生血管形成中起到重要作用。研究发现老龄患者接受肝切除术后肝再生能力明显减弱。老年LSECs结构和功能的异常可能是影响肝脏再生能力减退的主要原因之一，其具体机制不明。本项目拟通过体外LSECs与肝细胞共同培养、肝切除、部分肝脏移植的大鼠模型上，研究老年性LSECs的结构和功能改变对肝脏再生的影响。研究内容包括老龄肝脏LSECs血管内皮生长因子受体2及其下游靶基因的表达异常、细胞因子间的相互作用和调控网络变化在老年肝脏再生中的作用机制，并采用骨髓源性内皮祖细胞移植于模型动物体内，修复受损的老龄LSECs，以期改善老龄肝脏再生能力，进一步明确其可能的机制。此项工作将使我们对老龄肝脏再生功能减退的发病机制有深入地认识，为改善老龄肝再生、提高老龄供肝质量提供有效的检测和干预措施。为今后开发以LSECs为靶标的新型治疗方法提供理论依据和实验基础。

肝窦内皮细胞（LSECs）在肝脏再生的启动和新生血管形成中起到重要作用动物实验和临床研究均提示老龄患者接受肝脏切除术后肝脏再生能力和肝功能恢复明显减弱。老年LSECs结构和功能的异常可能是影响肝脏再生能力减退的主要原因之一，其具体机制尚未明确。本课题体外研究发现老年鼠LSECs内VEGF/VEGFR2及Id1、Wnt2和HGF表达较成年鼠和幼年鼠明显降低，将LSECs和原代肝细胞共培养，成年组LSECs较老年组LSECs虽未促进肝细胞增殖，但可以有效减少肝细胞的凋亡，说明老年LSECs对肝细胞的支持作用减弱。在肝切模型中，肝切术后肝细胞和LSECs增殖具有两相性，肝细胞增殖主要在术后前4天，2天时达峰，而LSECs在4天后开始增殖。老年LSECs内大量胶原沉积，表面窗孔结构消失，导致一些促肝脏再生的细胞因子无法透过肝窦进入肝细胞，进而影响肝细胞再生；另一方面，老年LSECs内VEGF/VEGFR2、VEGFR2/Id1及下游Wnt2、HGF表达下降，使老年肝脏再生能力减弱。采用带绿色荧光的骨髓源性祖细胞移植于肝切小鼠体内，发现移植的骨髓细胞可有效定植于肝脏内，多数位于肝窦部位，同时部分分化为LSECs，促进肝脏再生，并且支持肝功能，增加白蛋白分泌。本课题的顺利开展可促进我们对老龄肝脏再生功能减退的发病机制有深入地认识，为改善老龄肝再生、提高老龄供肝质量提供有效的检测和干预措施。为今后开发以LSECs为靶标的新型治疗方法提供了实验基础。在本基金的大力支持下，已共发表相关SCI文章6篇，培养研究生3名。

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