Atherosclerosis is a multifactorial, inflammatory disease that often progresses silently for decades and is complicated by unstable plaques that result in acute coronary syndromes and sudden cardiac arrest. Although current imaging technologies have made great strides to assign physical and structural parameters to assess the degree of plaque vulnerability, poor sensitivity and limited accuracy restrict their utility for precise diagnosis. The next challenge is to image molecular events of a plaque in real-time to determine the extent of plaque progression. To this end, we have recently engineered monocyte-targeting, peptide amphiphile micelles (MPAMs) through the incorporation of the chemokine receptor CCR2-binding motif (residues 13-35) of the monocyte chemoattractant protein-1 (MCP-1). Monocyte targeting is highly desirable as one of the early markers of plaque formation is the activation of endothelial cells which secrete MCP-1, recruiting monocytes in large quantities through their CCR2 receptor. More importantly, recent studies report the influx of monocytes continues throughout plaque progression and is proportional to the extent of atherosclerosis. Preliminary studies have confirmed biofunctionality of MPAMs in vitro, biocompatibility in vivo, and successful targeting to atherosclerotic plaques in ApoE knock-out mice assessed via optical imaging. With promising preliminary findings in hand, in the K99 phase, I will test the hypothesis that the development of a combinatorial, molecular-MR imaging tool by incorporating gadolinium to MPAMs provides a quantitative, noninvasive, in vivo detection system for plaque progression by binding to recruited monocytes. In the R00 phase, I propose the incorporation of the collagenase-1, or metalloproteinase-1 (MMP-1), cleavage site to attenuate plaque rupture and the utilization of these novels, multifunctional micelles in a murine model of vulnerable plaque. The ability to monitor the upregulation and the localization of monocytes will be possible and our investigations will lay the ground work for peptide amphihphile micelle-mediated theranostics for a library of molecular markers. In the K99 phase of this award, I will be mentored by the pioneer, peptide amphiphile expert and founding director of the Institute for Molecular Engineering at the University of Chicago, Dr. Matthew Tirrell. Supplemental to Dr. Tirrell's guidance, I will work closely with world-class cardiovascular clinicians and scientists such as Dr. James Liao and Dr. Godfrey Getz, who will ensure my progress aligns with making a relevant impact on cardiovascular biology and medicine. Furthermore, outstanding MRI researcher and clinician, Dr. Brian Roman and Dr. Seon-Kyu Lee, will guide my design for in vivo imaging. My K99 training will not only substantially enhance my knowledge and experience with diagnostic and therapeutic applications of my research, but will also be a vehicle to help locate an independent research position at a top research institute to complete the R00 phase of this award, and provide the initial support to prepare for my first R01 application. My long term goal is to become a leader in biomaterial design to tackle the challenges in cardiovascular disease.
Cardiovascular disease resulting from atherosclerosis is the leading cause of morbidity and mortality in the US and current imaging technologies do not have the accuracy for preventive measures. Here, the development of multifunctional nanoparticles with the ability to 1) bind to a specific molecular marker of atherosclerotic plaques 2) be detected using MRI, and 3) deliver a therapeutic agent is proposed. This advance would enable new diagnostic and therapeutic strategies for atherosclerosis.
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| Masehi-Lano, Jacqueline J; Chung, Eun Ji (2018) Engineering Citric Acid-Based Porous Scaffolds for Bone Regeneration. Methods Mol Biol 1758:1-10 |
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| Wang, Jonathan; Masehi-Lano, Jacqueline J; Chung, Eun Ji (2017) Peptide and antibody ligands for renal targeting: nanomedicine strategies for kidney disease. Biomater Sci 5:1450-1459 |
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