This project utilizes intratracheal instillation and breathing aerosols to deliver a variety of molecules, mediators, and drugs to the lungs of animals. Two parallel specific aims are proposed. In the first, we will answer key questions relating to how these delivery methods produce measured patterns of delivery to specified anatomic regions. We will also explore how the aerosolization process alters the proteins or carriers. In the second, we will apply these methods of drug delivery to animals with Pneumocystis carinii or cytomegalovirus infection.
Our specific aims are: 1. To improve pulmonary delivery of proteins and other therapeutic agents via the airways. This research will include: a. Analysis of instillation as a prelude and/or an alternative to aerosol delivery. b. Analysis of how aerosolization affects proteins and carriers. c. Analysis of the distribution and morphologic fate of deposited proteins in the lung. 2. To apply the above strategies to existing models of opportunistic lung infection. This research will include the following: a. Evaluation of potential upregulators of host defenses against Pneumocystis carinii. b. Evaluation of instillation vs. aerosol inhalation and the role of surfactant on spreading of drugs in the treatment of Pneumocystis carinii. c. Evaluation of instilled and aerosolized antiviral compounds (both a standard drug, ganciclovir, and novel antisense oligonucleotides) in relation to a murine CMV model. The proposed research will test key hypotheses central to the entire program. For example, the ability of IL-13 to upregulate the mannose receptor on lung macrophages and thus to enhance the clearance of Pneumocystis carinii from the lungs will be evaluated, a goal relevant to Project 0007. The potential of antisense oligonucleotides to treat cytomegalovirus infection will be tested, a goal relevant to Project 0010. We seek to develop data on how these and other molecules deposit and distribute within the lungs how they critically affect host defenses and how, in turn, that affects the fate of lung pathogens. The immediate goal is excellent science; the ultimate goal is new therapeutic strategies for opportunistic lung infections for human with AIDS.
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