Tissue ischemia is a consequence of vaso-occlusive sickle cell disease (SCO). In the current funding cycle,we identified an adverse, long-range consequence of localized ischemia in the sickle milieu:. SCO transformsand disseminates a localized, regional, and otherwise self-remitting ischemic insult into a systemic,nflammatory process attended by vaso-occlusion in distant and vital organs, and ultimately, increasedmortality. Tissue ischemia is thus not only a consequence of vaso-occlusive disease but is also a contributorto vaso-occlusion, inflammation, and other pathogenetic pathways in SCO. As in any diseased tissue,adaptive and maladaptive processes are entrained, and in this regard, we hypothesize that in SCO in theunstressed state and in the stressed, postischemic state, a triad of linked responses occurs, and consists ofinduction of heme oxygenase-1 (HO-1) and p21 as adaptive, protective responses, and induction ofmonocyte chemoattractant protein-1 (MCP-1) as a maladaptive, injurious process. This theme will bepursued in 4 specific aims:
Aim I : Hypothesis: The sickle milieu transforms and disseminates a transientepisode of localized ischemia into a systemic, long-range, inflammatory process with widespread vaso-occlusion and dysfunction of distant vital organs. Examination: Alterations in vital organs and tissues, andrelevant systemic indices will be analyzed in sickle mice in the unstressed state and following regionalischemia.
Aim II : Hypothesis: Induction of HO-1 is an adaptive, protective response in SCO in theunstressed state and following regional ischemia. Examination: Deficiency of HO-1. in the endothelium andkidney using a Cre/lox approach will exacerbate injury in these sites in sickle mice in the unstressed stateand following regional ischemia.
Aim III : Hypothesis: Induction of MCP-1 (a HO-suppressible gene) is amaladaptive, injurious response in SCO in the unstressed state and following regional ischemia.Examination: Approaches that interrupt either the expression of MCP-1 gene or the efficacy of the MCP-1protein will decrease tissue injury in sickle mice in the unstressed state and following regional ischemia.
AimI V: Hypothesis: Induction of p21 (an HO-inducible protein) is an adaptive, protective response in SCO in theunstressed state and following regional ischemia. Examination: Deficiency of p21, as modeled by p21 -/-mutant mice, will exacerbate tissue injury in sickle mice in the unstressed state and following regionalischemia.LAY SUMMARY: Decreased blood supply to tissues contributes to organ and tissue damage in sickle celldisease. This application proposes to study how this occurs, and the genes that are induced, specifically,those such as MCP-1 that contribute to injury, and those such as HO-1 and p21 that protect against suchinjury. Such information may assist in devising new treatments for sickle cell disease.
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