PROJECT SUMMARY/ABSTRACT Inflamed thin-cap fibroatheromata (TCFA), unstable lesions in 60-70% of coronary artery disease (CAD), are prone to rupture and result in substantial morbidity and mortality worldwide. Thus, early clinical diagnosis and effective risk stratification of these lesions has the potential to improve management of CAD and prevent its progression to catastrophic events such as heart attack and stroke. However, the small size and complex morphological/biological features of TCFA make early detection and risk assessment difficult. These challenges have spurred a five-year research plan to develop a superior catheter-based tri-modal “Intravascular Microscopic Radioluminescence Photoacoustic Imaging (IMRPI)” system to detect and outline coronary TCFA with quantitative information of plaque compositions including intraplaque hemorrhage (a stroke marker). The new tool will also be able to provide morphological and histopathological information at sub-cellular resolution in real-time. This project will be built on Dr. Zaman’s background as an Electrical and Biomedical Engineer with expertise in development of novel imaging systems. Furthermore, the feasibility of this proposed study is based on Dr. Zaman’s published data funded by NIH-K99/R00 award, where she built a novel Circumferential Intravascular Radioluminescence Photoacoustic Imaging (CIRPI) system to successfully detect and characterize TCFA in ex vivo murine/human carotid and in vivo rabbit abdominal aortic arteries. In this proposal, the IMRPI system will be developed by reengineering the CIRPI system to be miniaturized with micro-optical components so that a dual-axis confocal microscope (DACM) can be implemented in the endoscopic probe. Dr. Zaman has assembled exceptional collaborators/consultants/other significant contributors who are leading experts in photoacoustic tomographic imaging/image reconstruction, ultrasound transducer design/manufacturing, dual-axis-confocal microscope endoscopy and micro-optical design/system development, MEMS design/fabrication, interventional cardiology, pathology, and cardiovascular imaging. The Specific Aims focus on the design/development of the IMRPI system followed by testing in (1) ex vivo human carotid and coronary plaques from carotid endarterectomy and postmortem autopsy specimen, (2) in vivo pig coronary atherosclerotic models, and (3) discarded fresh human hearts. These results will be further validated with clinical optical coherence tomography (OCT), intravascular ultrasound (IVUS), and computed tomography (CT), followed by autoradiography and histochemical analysis. Collectively, the proposed research will elucidate an advanced endoscope design to detect, outline, and characterize vulnerable plaques in coronary arteries by revealing sub-cellular aspects of plaque morphology and histopathology, and will therefore, constitute a valuable indispensable ally in this challenging quest to aid in early detection and risk assessment to...