This bioengineering research partnership will develop a dual-modality CT/SPECT system for high-resolution imaging of radionuclides in transgenic and knockout mice that now are in widespread use to model the mechanism, diagnosis, and treatment of human diseases. This research will be focused on the development of techniques that correlate structure and function, and that can perform noninvasive and quantitatively accurate measurement of tissue metabolism and organ physiology in small animals using radiolabeled tracers. Within this context, the research program includes 5 specific aims. (1) A pinhole SPECT system will be developed using a pixellated silicon pixel array and thallium-doped cesium iodide (CsI(Tl)) scintillator for radionuclide imaging of small animals. Two interchangeable detector arrays will be developed, one for imaging low-energy radionuclides such as '25I (27.5 keV), and the other for imaging 99mTc (140 keV) and other radionuclides having higher photon energies. (2) The pinhole SPECT system from Specific Aim 1 will be integrated with a cone-beam computed tomography system volume to allow sequential acquisitions of CT and SPECT images without moving the animal. (3) Cone-beam tomographic algorithms will be implemented for reconstruction of the radionuclide and x-ray tomographic data from the small animal imager. Techniques will be developed that use the reconstructed CT and SPECT data to quantify regional distribution of radionuclide concentration at spatial resolutions suitable for mice. (4) The dual-modality imaging system will be used for in vivo measurement of cardiovascular physiology in transgenic mice to investigate the role of the sympathetic innervation in heart disease. These measurements will test the hypothesis that increased heterogeneity of sympathetic innervation is related to the development of congestive heart failure. (5) The dual-modality imaging system will be used to measure the tumor and organ distribution of humanized anti-HER2 monoclonal antibody in a transgenic mouse model of metastatic breast cancer. The overall goal of this project wil1 develop a high-resolution imaging system that combines CT and SPECT to correlating structure and function. The system also will be designed to perform noninvasive serial studies in mice, and to replace invasive direct tissue sampling and autoradiography for biodistribution studies and functional assessments using radiolabeled tracers in transgenic mice.
