This proposal describes a 5 year mentored program for the development of an academic career in Pulmonary Medicine. The Principal Investigator has recently completed fellowship training in Pulmonary and Critical Care Medicine at Johns Hopkins University where she acquired extensive training in the use of cell and molecular techniques to investigate vascular pathobiology. She will extend her scientific skills through continuation of her work into animal models of disease. The co-sponsors of the program, Drs. Crow and Hassoun, are both experts in vascular biology, with Dr. Crow having expertise in the molecular biology of apoptosis and Dr. Hassoun in animal models of acute lung injury (ALI). Both provide the candidate with an excellent environment to accomplish the goals of this proposal. The research will focus on the molecular determinants of endothelial cell (EC) apoptosis in ALI and the physiological consequences of this mode of vascular injury. ALI has a substantial impact on public health accounting for 75,000 U.S. deaths per year. Mortality rates are 30-60% and treatment remains supportive only. A greater understanding of the molecular and cellular determinants of the disease is necessary to identify new therapeutic targets. The Pi's work demonstrates that ALI induced by intratracheal exposure to the bacterial toxin lipopolysaccharide (LPS) is associated with early EC apoptosis in the lung and vascular leak. Further, her work demonstrates that macrophage migration inhibitory factor (MIF) is a determinant of EC responses to LPS. MIF antagonizes LPS-induced apoptosis, in part, through its role in regulating the inhibitor of apoptosis, FLICE-like Inhibitory Protein (FLIPs). This proposal will characterize the physiologic effects of EC apoptosis on vascular dysfunction in a direct lung injury model of ALI and the contributions of MIF and FLIPs in the regulation of this mechanism of vascular injury. The initial aim focuses on the contribution of EC apoptosis to ALI in a direct lung injury model of disease.
The second aim defines the impact of MIF deficiency on vascular dysfunction in vivo and in culture.
The final aim defines the mechanism by which MIF regulates FLIPs and its effects on LPS-induced apoptosis. These studies will improve our understanding of the factors regulating apoptosis in ALI, information that could lead to new therapies.
