Sepsis remains a current medical challenge. The frequency of this devastating disease is increasing and is associated with a death rate as high as 70%. It is often exacerbated by edema, which promotes fluid accumulation in tissues, causes an enhanced inflammatory response and induces fibrosis. Over time this can lead multiple organ failure and death. Currently there are no therapies for blocking vascular leakage in sepsis. This is primarily because the molecular mechanisms regulating vascular permeability are not completely understood. Focusing on the mechanisms of vascular permeability would potentially provide valuable targets for therapeutic intervention to prevent inflammation and edema due to sepsis. We have identified a novel mechanism by which vascular barrier integrity is maintained. The primary goal of this proposal is to elucidate this mechanism further and thereby identify potential new therapeutic targets. We have previously reported an interaction between RRas and Filamin A (FLN). RRas, an intracellular GTP-binding protein, is primarily expressed in endothelial cells in vivo and is a regulator of arterial endothelial function. The cytoskeletal protein FLN is required for cell-cell contact in vascular development. Indeed, FLN-null mice die of vascular defects. We have recently reported that in arterial endothelial cells endogenous RRas interacts with endogenous FLN. Furthermore, endothelial barrier function is dependent upon active RRas and an association between RRas and FLN. Thus, we propose the innovative hypothesis that the RRas and FLN complex is a primary driver in maintaining endothelial barrier function. This proposal will focus on the RRas and FLN complex as a point of integration between several select signaling pathways involved in regulating vascular permeability. This study will test whether this RRas is a therapeutic target in preclinical mouse models of sepsis.
The cellular mechanisms regulating sepsis-initiated vascular permeability are not yet completely known and there are no therapies available that block vascular leakage in sepsis. We have identified a novel mechanism by which vascular barrier integrity is maintained. We propose that the association of RRas with Filamin A may regulate vascular permeability. We will test whether this complex is a therapeutic target in preclinical mouse models of sepsis.
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