Liver Sinusoidal Endothelial Cell Progenitor Cells.

描述（由申请方提供）：有两个肝窦内皮细胞（LSEC）祖细胞群。骨髓中的LSEC祖细胞在肝损伤的修复和促进肝再生中起重要作用，但在正常代谢中不起作用。肝脏中的LSEC祖细胞（驻留LSEC祖细胞）对肝损伤的修复和促进肝再生的贡献小得多，但却是正常LSEC周转的祖细胞。该提案的总体目标是阐明LSEC祖细胞功能障碍和祖细胞修复的潜在机制，目的是确定治疗靶点。具体目的1基于以下假设：骨髓LSEC祖细胞募集的调节（即骨髓中LSEC祖细胞的增殖、祖细胞从骨髓向循环的动员以及在肝脏中的植入）在慢性肝病中受损，并且这种修复过程的受损增加了急性肝损伤的损害，并损害了慢性肝病中的肝再生。研究将检查慢性肝病中急性损伤对骨髓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子，并确定祖细胞治疗是否减弱急性损伤。具体目标2的假设是，急性肝损伤改变了信号通路 用于骨髓LSEC祖细胞在肝脏中的移植。研究将检查改变的信号传导对骨髓LSEC祖细胞植入和肝再生的影响，阐明导致信号传导受损的机制，并将确定恢复正常信号传导的策略是否改善急性损伤。第三个目标的假设是 LSEC的表型变化与衰老是由于常驻祖细胞的变化。研究将确定LSEC的变化是否确实是由于祖细胞的变化，并将检查导致常驻祖细胞变化的信号通路。

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.