The mission of our Biomedical Technological Research Center (BTRC) is to develop innovative magnetic resonance and optical imaging technologies for biomedical research. In this competitive supplement to our grant, we are requesting support for developing novel imaging technologies for measuring creatine kinase (CK) metabolism in the myocardium. Heart disease is the leading cause of death in the US with $316 billion in healthcare costs in 2010. The molecular changes associated with the CK reaction play vital role in the myocardial energetics. Noninvasive imaging of CK metabolism has the potential to identify patients with coronary artery disease at various stages in the disease process. Specifically, the tissue CK metabolites may serve as clinically useful biomarkers for the energy deprivation in the failing heart and local viability in ischemic injury. Currently, 31 P and1 H magnetic resonance spectroscopy (MRS) methods are used to measure CK metabolism;however, the inherent limitations of these methods are low resolution and long acquisition times. Accordingly, the overarching goals of this proposal are to address this unfulfilled need for high resolution imaging of these metabolites in vivo. Specifically, we exploit the differences in exchange rates of amine protons on CK metabolites to develop a novel class of MR imaging techniques to spatially map myocardial creatine (Cr) in this proposal. The effects of chemical exchange saturation transfer (CrEST) and exchange enhanced relaxation times (EXERT) on bulk water will be explored. Both theoretical design and experimental validation of both methods will be carried out on physiological phantoms and myocardial tissue. Time efficient MRI pulse sequences that integrate cardiac and respiratory gating schemes will be developed and implemented for in vivo applications. These developments will be driven by two driving biomedical projects (DBP) from our collaborators that serve as test beds for the proposed development and validation. Once validated, the techniques will provide noninvasive imaging assays for mapping high-energy phosphate metabolism in the ongoing studies of the DBPs. These methods neither involve any radiation nor require any exogenous contrast agents. They provide ~2 orders of sensitivity advantage over conventional MRS and can be readily implemented in a clinical setting. Successful accomplishment of the aims of this proposal will lead to molecular imaging techniques for assessing myocardial metabolism, which would have great potential to enhanced patient care.

Public Health Relevance

PUBLIC RELEVANCE: Heart disease is the leading cause of death in the US. Since the creatine kinase (CK) reaction plays a vital role in the myocardial energetics, the molecular aberrations associated with the CK reaction are implicated in the most common and important forms of heart disease. In this competitive supplement, we propose to develop a novel class of techniques for noninvasive imaging of endogenous free creatine (Cr). The successful accomplishment of the goals of this proposal will lead to molecular imaging techniques for assessing myocardial high-energy phosphate metabolism, which potentially contribute to enhanced patient care.

National Institute of Health (NIH)
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Biotechnology Resource Grants (P41)
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Special Emphasis Panel (ZRG1-SBIB-N (40))
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Liu, Christina
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University of Pennsylvania
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