Endothelial repair response to liver injury.

描述(由申请人提供)：对肝窦内皮细胞的损伤是肝窦阻塞综合征(以前称为静脉闭塞症)和冷保存损伤的关键起始成分，并导致对乙酰氨基酚中毒。在其他器官中，已经证明血管内皮细胞的修复部分是通过招募预先存在的内皮细胞，部分是通过招募内皮祖细胞。也有研究表明，循环内皮祖细胞的数量显著增加，以响应血管损伤。这项拨款提案的假设是，内皮祖细胞替代受损的肝窦内皮细胞是肝损伤严重程度的决定因素，而肝损伤源于肝窦内皮细胞。如果这是真的，那么不良的内皮祖细胞反应将加重肝脏损伤，而增强的前体细胞对正弦内皮细胞损伤的反应将改善肝脏损伤。这一假说将通过3个实验模型中的3个特定目标进行验证。具体目的1.确定骨髓源性内皮祖细胞是否能修复肝窦内皮细胞的损伤。2.确定骨髓抑制与内皮祖细胞反应减弱是否加剧了起源于肝窦内皮细胞的肝损伤的严重程度。3.研究增强内皮祖细胞反应是否改善肝损伤的转归。如果这些研究按照描述的那样进行，并证实了工作假说，这将为未来使用促进内皮祖细胞反应的药物进行治疗试验提供基础。

DESCRIPTION (provided by the applicant): Injury to sinusoidal endothelial cells is a key, initiating component of sinusoidal obstruction syndrome (formerly known as venoocclusive disease) and of cold preservation injury, and contributes to acetaminophen toxicity. In other organs it has been shown that repair of vascular endothelium is partially through recruitment of pre-existing endothelial cells and partially through recruitment of endothelial progenitor cells. It has also been shown that there is a marked increase in the number of circulating endothelial progenitor in response to vascular injury. The hypothesis for this grant proposal is that replacement of damaged sinusoidal endothelial cells by endothelial progenitor cells is a determinant of the severity of liver injury that originates in the sinusoidal endothelial cells. If this is true, then liver injury will be worsened by a poor endothelial progenitor cell response and improved by an enhanced progenitor cell response to sinusoidal endothelial cell injury. This hypothesis will be examined by 3 specific aims in 3 experimental models. Specific Aim 1. Determine whether damage to sinusoidal endothelial cells is repaired by bone marrow-derived endothelial progenitor cells. 2. Determine whether bone marrow suppression with a diminished endothelial progenitor cell response exacerbates the severity of liver injury that originates in sinusoidal endothelial cells. 3. Examine whether boosting endothelial progenitor cell response improves the outcome of liver injury. If the studies are performed as described and confirm the working hypothesis, this would provide the basis for future therapeutic trials using agents that boost the endothelial progenitor cell response.