Atherosclerosis and atherosclerosis related complications such as heart attack, stroke, and angina, are the leading cause of death in the western world, and effective treatments are greatly needed. A key issue limiting the treatment of atherosclerosis is an inability to diagnose atherosclerotic plaques that have a high risk of growing and rupturing, also known as "active" plaques. The overproduction of reactive oxygen species (ROS) is necessary for the growth and rupture of atherosclerotic plaques, making ROS an excellent diagnostic marker for "active" plaques. The objective of this application is to develop a new family of fluorescent contrast agents, termed the hydrocyanines, which have the physical and chemical properties needed to image ROS in atherosclerotic plaques, in the carotid artery, and detect plaque activity. The hydrocyanines are a new family of fluorescent dyes, recently developed in our laboratory, which can detect ROS at nanomolar concentrations, have tunable emission wavelengths ranging from 570-810 nm, and accumulate within cells after oxidation. Our approach is to image ROS in the carotid artery of mice and rabbits, suffering from vascular injury and atherosclerosis, with the hydrocyanines. The central hypothesis of this proposal is that: The hydrocyanines have the physical and chemical properties needed to detect oxidative stress in the carotid artery and detect plaque activity. This hypothesis is based on our preliminary data, which demonstrates that the hydrocyanines can detect superoxide and the hydroxide radical in cell culture, in tissue samples and for the first time in vivo. The overall objective of this proposal will be accomplished by testing our central hypothesis through the following three Specific Aims;
Specific Aim I : Optimize the hydrocyanines using the kinetic isotope effect Specific Aim II: Detect ROS production in a murine model of carotid artery injury Specific Aim III: Detect ROS production by atherosclerotic tissues in vivo in a rabbit model of atherosclerosis and ex-vivo in diseased human coronary arteries The experiments in this proposal will determine if the hydrocyanines can image ROS in atherosclerotic plaques and detect plaque activity in mice and rabbits. The experiments in this proposal are innovative because they will lead to the development of a contrast agent that can image ROS, in vivo, for the first time. This proposal is also significant because it will generate a new class of diagnostics, which have the potential to diagnose patients at risk of developing heart attacks and strokes. Furthermore, numerous other diseases are also associated with an overproduction of ROS, such as cancer and neurodegenerative disease;we therefore anticipate that the results of this proposal will impact several areas of medicine and biology.
Project Narrative The experiments in this proposal will lead to the development of a new class of fluorescent dyes, termed the hydrocyanines, which can image reactive oxygen species in vivo. The major applications of the hydrocyanines are to diagnose patients at risk of developing heart attacks and strokes. Numerous other diseases such as cancer and arthritis can also be diagnosed by imaging reactive species;we therefore anticipate that the results of this proposal will impact several areas of medicine and biology.
|Acharya, Abhinav P; Rafi, Mohammad; Woods, Elliot C et al. (2014) Metabolic engineering of lactate dehydrogenase rescues mice from acidosis. Sci Rep 4:5189|
|Hermann, Christopher D; Wilson, David S; Lawrence, Kelsey A et al. (2014) Rapidly polymerizing injectable click hydrogel therapy to delay bone growth in a murine re-synostosis model. Biomaterials 35:9698-708|
|So, Hongyun; Lee, Kunwoo; Seo, Young Ho et al. (2014) Hierarchical silicon nanospikes membrane for rapid and high-throughput mechanical cell lysis. ACS Appl Mater Interfaces 6:6993-7|
|Acharya, Abhinav P; Nafisi, Parsa M; Gardner, Austin et al. (2013) A fluorescent peroxidase probe increases the sensitivity of commercial ELISAs by two orders of magnitude. Chem Commun (Camb) 49:10379-81|
|Dasari, Madhuri; Acharya, Abhinav P; Kim, Dongin et al. (2013) H-gemcitabine: a new gemcitabine prodrug for treating cancer. Bioconjug Chem 24:4-8|
|Leoni, Giovanna; Alam, Ashfaqul; Neumann, Philipp-Alexander et al. (2013) Annexin A1, formyl peptide receptor, and NOX1 orchestrate epithelial repair. J Clin Invest 123:443-54|
|Reddie, Khalilah G; Humphries, William H; Bain, Charlo P et al. (2012) Fluorescent coumarin thiols measure biological redox couples. Org Lett 14:680-3|
|Willett, Nick J; Kundu, Kousik; Knight, Sarah F et al. (2011) Redox signaling in an in vivo murine model of low magnitude oscillatory wall shear stress. Antioxid Redox Signal 15:1369-78|
|Selvam, Shivaram; Kundu, Kousik; Templeman, Kellie L et al. (2011) Minimally invasive, longitudinal monitoring of biomaterial-associated inflammation by fluorescence imaging. Biomaterials 32:7785-92|
|Ning, Xinghai; Lee, Seungjun; Wang, Zhirui et al. (2011) Maltodextrin-based imaging probes detect bacteria in vivo with high sensitivity and specificity. Nat Mater 10:602-7|
Showing the most recent 10 out of 12 publications