Endothelial repair response to liver injury

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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.