Liver Sinusoidal Endothelial Cell Progenitor Cells.

描述（由申请人提供）：肝窦内皮细胞（LSEC）祖细胞有两种。骨髓中的LSEC祖细胞在肝损伤修复和促进肝脏再生中发挥重要作用，但在正常的肝脏更新中没有作用。肝脏中的LSEC祖细胞（常驻LSEC祖细胞）在修复肝损伤和促进肝脏再生方面的作用要小得多，但却是正常LSEC周转的祖细胞。本研究的主要目的是阐明LSEC祖细胞和祖细胞修复功能障碍的机制，以确定治疗靶点。具体目标1基于以下假设：慢性肝病患者对骨髓LSEC祖细胞募集的调节（即LSEC祖细胞在骨髓中的增殖、祖细胞从骨髓向血液循环的动员和在肝脏中的植入）受到损害，这种修复过程的损害增加了急性肝损伤的损害，并损害了慢性肝病患者的肝脏再生。研究将检查慢性肝病急性损伤对骨髓LSEC祖细胞向肝脏募集的影响，建立祖细胞募集不足风险的预测因素，并确定祖细胞治疗是否能减轻急性损伤。具体目标2的假设是急性肝损伤改变了信号通路

DESCRIPTION (provided by applicant): There are two populations of liver sinusoidal endothelial cell (LSEC) progenitor cells. The LSEC progenitor cells in the bone marrow play an important role in repair of liver injury and promoting liver regeneration, but play no role in norml turnover. The LSEC progenitor cells in the liver (resident LSEC progenitor cells) contribute much less to repair of liver injury and promoting liver regeneration, but are the progenitors for normal LSEC turnover. The overarching objective of this proposal is to elucidate mechanisms underlying dysfunction of LSEC progenitor cells and of progenitor cell repair with the goal of identifying therapeutic targets. Specific aim 1 is based on the hypothesis that regulation of recruitment of bone marrow LSEC progenitor cells (i.e. proliferation of LSEC progenitors in the bone marrow, mobilization of progenitors from bone marrow to the circulation, and engraftment in the liver) is impaired in chronic liver disease and that this impairment of a repair process increases the damage of acute liver injury and impairs liver regeneration in chronic liver disease. Studies will examine the effect of acute injury in chronic liver disease on bone marrow LSEC progenitor cell recruitment to the liver, establish predictors for the risk of inadequate progenitor cell recruitment, and determine whether acute injury is attenuated with progenitor cell therapy. The hypothesis for specific aim 2 is that acute liver injury alters the signaling pathways for bone marrow LSEC progenitor cell engraftment in the liver. Studies will examine the effect of altered signaling on bone marrow LSEC progenitor cell engraftment and on liver regeneration, elucidate the mechanisms that lead to the impairment of signaling, and will determine whether strategies to restore normal signaling ameliorate acute injury. The hypothesis for the third aim is that phenotypic changes in LSEC with aging are due to changes in resident progenitor cells. Studies will determine whether the changes in the LSEC are indeed due to changes in the progenitor cell and will examine the signaling pathways that lead to the changes in the resident progenitor cells.