We propose to develop technologies for delivering foreign genes to intact animals. Delivery and expression of these genes will be targeted to cell populations critical t o the pathogenesis of acute lung injury. We will design and produce liposomes which target lung endothelium, lung epithelium, alveolar macrophages or liver. We will study the behavior of these liposomes in vivo and test their ability to target DNA in the form of plasmids to the desired site. We will design and construct plasmid expression vectors the delivery of which results in optimal expression of transgenes at sites critical to the development and progression of lung injury. Strategies will include 1) use of promiscuous promoter regions; 2) use of regulatory regions which respond specifically to endotoxin or tumor necrosis specific regulatory regions (dominant control regions) to target expression to the liver. Because some prostanoids may modulate acute lung injury, we will also use these technologies to deliver sense and antisense cDNA for prostaglandin (PG) G/H synthase to lung endothelium, lung epithelium, or alveolar macrophages and determine the effects of hyperexpression of these constructs on responses to endotoxin in cultured cells and intact animals. Because we postulate that liver production and release of xanthine dehydrogenase/oxidase (XD/XO) contributes to oxidant stress in acute lung injury, we will use these technologies to deliver sense or antisense cDNA for XD to the liver and determine effects on generation of XD/XO. The ultimate goal of these studies is to develop a new approach to the prevention and therapy of acute lung injury in humans using the techniques of gene transfer.
NIH ExPorter
NIH ExPorter