Heme oxygenase (HO) metabolizes heme to biliverdin during which iron is released and carbon monoxide (CO) emitted. In 1992, the PI's laboratory provided the first evidence for the cytoprotective effects of HO-1, findings that served as the basis for the first cycle of funding beginning in 1993, for the Parent R01 (DK47060). The current cycle of the Parent R01, funded as an R37 from 2007-2012, investigates the functional significance of induction and inducers of HO-1, and the mechanisms whereby HO-1 serves as a protectant against tissue injury; specific aims include the analysis of mechanisms whereby HO-1 protects against lipopolysaccharide (LPS)-induced inflammation (AIM II), and mechanisms whereby HO-1 protects against renal ischemia-induced apoptosis and inflammation (AIM III). A recently recognized potent inducer of HO-1 is erythropoietin (EPO). EPO is a potent stimulator of erythrocyte production and is now an established therapy for anemia in chronic kidney disease and other conditions. However, a most remarkable and entirely unexpected effect of EPO has recently been demonstrated: namely, the cytoprotective properties of EPO in the kidney, heart, and other tissues, which enable EPO to suppress inflammation and prevent apoptosis. These cytoprotective effects of EPO are not due to increases in hematocrit, and reflect intracellular processes that remain poorly understood. We hypothesize that the induction of HO-1 by EPO accounts for the anti-inflammatory and anti-apoptotic effects of EPO. Aim I of the proposed supplement is based on, and aligns with, Aim II of the parent grant, and will test whether HO-1 is the mechanism whereby EPO protects against LPS-induced inflammation. Aim II of the proposed supplement is based on, and aligns with, Aim III of the parent grant, and will test whether HO-1 is the mechanism whereby EPO protects against renal ischemia-induced apoptosis. Defining the role of HO-1 in mediating the protective effects of EPO may facilitate the development of analogues of EPO that preferentially recruit cytoprotective pathways, and would assist in identifying those clinical settings which would likely respond to the protective effects of EPO. This Administrative Supplement, if awarded, would assist in creating a new research technician position to examine HO-1 as the basis for the protective effects of EPO.