The Role of MIF in Endothelial Apoptosis

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DESCRIPTION (provided by applicant): Endothelial cell (EC) injury is a cardinal feature of sepsis. MIF, a cytokine elevated both in the circulation and endothelial cells during sepsis, plays a critical role in the pathophysiology of this disease. Studies in our lab and others demonstrate that human EC display a high resistance to apoptotic stimuli consistent with the upregulation of anti-apoptotic pathways. We hypothesize that MIF functions to block apoptosis in these EC. The goal of this study is to characterize the role of MIF in endothelial cell apoptosis and activation via the following aims: In SA #1 we will characterize apoptosis in human pulmonary artery endothelial cells (HPAEC) deficient in MIF using two approaches 1) we will downregulate MIF production in HPAEC using RNA interfering technology, and 2) we will disrupt MIF-receptor interactions with neutralize antibodies. The susceptibility of MIF-expressing and MIF-deficient HPAEC to apoptotic stimuli will then be tested using hypoxia, chemic/reperfusion, TNF, and endotoxin treatment. In SA#2 we define known and novel responses to MIF stimulation in HPAEC. Finally, we will characterize the apoptotic pathways exposed in the absence of MIF in SA#3.