Although it is already clear that positron emission tomographic (PET) imaging can be used to follow transgene expression in whole animals, no studies to date have yet demonstrated the utility of using molecular imaging methods, such as PET, to follow transgene expression in experimental models of disease. We propose to address this important issue by administering, to rats, adenoviral vectors carrying biologically relevant genes (shown previously by collaborators to affect the pathophysiology of different disease models of the acute respiratory distress syndrome, ARDS, and of pulmonary hypertension) and a """"""""PET reporter gene"""""""" (e.g. viral thymidine kinase, tk), both under the control of the same promoter. Imaging will be performed to follow the location (within the lungs), timing (onset and duration), and magnitude of reporter transgene expression in relation to the physiologic effects (also studied with non-invasive imaging) of the disease modifying genes. Thus, our proposal has the following specific aims:
Specific Aim 1 : using PET imaging, determine the timing, magnitude, duration, and functional effects of beta-2 adrenergic receptor (beta2AR) transgene expression during experimental lung injury. 1.a Measure changes with PET and in vitro assays of beta2AR and tk expression as a function of viral dose. 1.b Determine the time course of gene expression with PET in normal animals. 1.c Correlate (temporally and geographically, i.e. within the lungs) PET reporter gene expression, beta-2 adrenergic receptor transgene expression, and functional effects of the beta2AR transgene (also evaluated with PET imaging) in acute hyperoxic lung injury (a lung injury model of ARDS).
Specific Aim 2 : using PET imaging and echocardiography, determine the timing, magnitude, duration, and functional effects of prostaglandin I2 synthase transgene expression during experimental pulmonary hypertension. An analogous series of studies (Specific Aims 2.a, 2.b and 2.c) will be implemented in two variants of the monocrotaline model of pulmonary hypertension, a model of sub-acute pulmonary vascular disease. The results will demonstrate how PET imaging can be used to study the impact of changes in gene expression on the natural history of disease or to develop therapeutic protocols to alter disease outcome.
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