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Accordingly, the specific aims are: <ol>
<li> Determination of HBEC sensitivity to the cytotoxic and protein synthesis inhibitory effects of Stx-1; </li>
<li> Determination of inflammatory factor regulation of the cytotoxic effect of Stx-I in HBEC; </li>
<li> Determination of the source(s) of inflammatory cytokines that affect HBEC responsiveness to Stx-1, focusing on HBEC and circulating white blood cells; and </li>
<li> Determination of the effects of Stx-1 on HBEC that could lead to CNS dysfunction in HUS, including mechanisms of cytotoxicity, regulation of vasoactive factor production, and modulation of platelet adherence.</li></ol></p>
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HUS is the leading cause of acute renal failure in children and is characterized by renal injury, microangiopathic hemolytic anemia, and thrombocytopenia. Although the kidney is an initial target in HUS, those patients who die from the disease do so primarily from brain, not renal, involvement. There is, however, very little understanding of how the central nervous system is affected in this disorder. </p>
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HUS is associated with enteric infection by Shiga toxin (Stx) producing E. coli. The toxin binds to cells expressing a specific glycosphingolipid cell surface Stx receptor (Gb3) whereupon it may exert a variety of effects, including inhibition of protein synthesis, induction of apoptosis, regulation of vasoactive factor production, and others. </p>
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Generally, these studies have focused on cells thought to be primary targets in HUS, namely, renal cells. Very little work, however, has been done on how Stx affects the brain. Preliminary studies from our laboratory indicate that human brain microvascular endothelial cells (HBEC) might be targets of Stx action. Further, these studies suggest that HBEC may respond to Stx and factors likely to be present in the setting of HUS in highly unique manner. </p>
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Based on these findings, the following hypothesis has been formulated: Unlike renal endothelial cells, HBEC are not normally sensitive to Stx. Soluble or cell-associated members of the inflammatory cytokine superfamily, derived from circulating white blood cells or endothelial cells themselves, cause massive upregulation of Stx responsiveness in HBEC. Such upregulation leads to enhanced white blood cell and possibly platelet adhesion, endothelial cell apoptosis and necrosis, and altered vasoactive factor production. The unique responsiveness of HBEC to cytokine upregulation of Stx-1 sensitivity may provide the basis for therapeutic interventions aimed at blocking cytokine actions on the brain. </p>