Mehran M Sadeghi, MD

Despite remarkable recent progress in molecular and vascular biology research, little has been achieved in adapting traditional imaging modalities to detect molecular pathobiology in vivo. Molecular imaging provides a unique opportunity to link vascular and molecular biology and imaging, ultimately leading to the development of novel imaging approaches, both for research and clinical diagnostics. The ultimate goal of research in my laboratory is to develop novel imaging approaches to detect the molecular pathobiology of the vessel wall in vivo. Our comprehensive approach includes several components. Through basic vascular biology research we identify relevant molecular processes and potential targets for imaging (and therapeutics). Next, we use the state of the art technology to develop novel tracers targeted at relevant molecular markers, and establish molecular vascular imaging protocols in animal models of human disease. Finally, we exploit these techniques to further advance vascular biology and clinical research. We have made significant progress towards achieving these goals in the past few years. Specifically, we have focused on vascular remodeling, as the prototypic pathological vascular process shared by many vascular diseases, including atherosclerosis, graft arteriosclerosis, post-angioplasty restenosis, and aneurysm formation. Our federally funded studies of the pathophysiology of vascular remodeling in graft arteriosclerosis, performed under the umbrella of the Interdepartmental Program in Vascular Biology and Transplantation at Yale have led to the identification novel molecular markers, including a neuropilin-like protein, ESDN, as a potential target for diagnosis and therapy of vascular remodeling. We have demonstrated that ESDN is upregulated in vascular remodeling, and have defined its function as regulator of vascular cell proliferation in vivo. We are currently in the process of defining other aspects of ESDN function, including its role in growth factor and integrin signaling pathways, and identification of ESDN ligands. In molecular imaging arena, we have identified and validated avß3 integrin activation as a target for imaging the proliferative process in vascular remodeling, and have demonstrated the suitability of avß3-targeted tracers for imaging graft arteriosclerosis. Matrix metalloproteinase (MMP) activation, as a key regulator of vascular remodeling, was targeted for in vivo imaging of injury-induced vascular remodeling and aneurysm formation using high resolution microSPECT imaging in conjunction with CT angiography for anatomical localization. We are currently in the process of optimizing the technical aspects of in vivo microSPECT/CT imaging to improve visualization and quantitation of molecular targets. In parallel, we have developed a novel “tracer design” concept for in vivo applications and have been involved in the development of a novel intravascular detection system which combines scintigraphy with high resolution optical coherence tomography imaging.

• Molecular Imaging of Vascular and Valvular Remodeling
• Molecular Imaging of Plaque Vulnerability and Aneurysm
• Neuropilin-like Proteins in Vascular Remodeling