Endothelial repair response to liver injury

描述（由申请方提供）：窦内皮细胞损伤是窦阻塞综合征（以前称为静脉闭塞性疾病）和冷保存损伤的关键起始组分，并导致对乙酰氨基酚毒性。在其他器官中，已经表明血管内皮的修复部分通过募集预先存在的内皮细胞，部分通过募集内皮祖细胞。也已经表明，响应于血管损伤，循环内皮祖细胞的数量显著增加。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窦内皮细胞起源的肝损伤严重程度的决定因素。如果这是真的，那么肝损伤将因内皮祖细胞反应不良而恶化，并因祖细胞对窦状隙内皮细胞损伤的反应增强而改善。这一假设将在3个实验模型中通过3个具体目标进行检验。具体目标1。确定骨髓来源的内皮祖细胞是否修复窦内皮细胞的损伤。2.确定骨髓抑制伴内皮祖细胞反应减弱是否会加重肝窦内皮细胞源性肝损伤的严重程度。3.检查增强内皮祖细胞反应是否改善肝损伤的结果。如果这些研究如所述进行并证实了工作假设，这将为未来使用增强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.