""""""""Epigenetics"""""""" refers to changes in phenotype or gene expression caused by mechanisms other than changes in the underlying DNA sequence. Abnormal epigenetic control mechanisms are now regarded as significant contributing factors to the pathophysiology of different diseases, including cancer. The main epigenetic mechanisms that induce phenotypic changes in mammalian cells are DNA methylation, histone methylation and histone acetylation. Many recent targeted drug development efforts have been directed towards the modification of one or more of these epigenetic mechanisms. In that regard, several cell culture based assays are being used to analyze different epigenetic processes, and small molecule drugs modulate these epigenetic processes. However these tests are not capable of predicting the exact behavior of drug pharmacokinetics and pharmacodynamics in living subjects. The current intense efforts to develop such drugs, as well as an ever increasing interest in epigenetics research, creates a paramount need to develop new more meaningful molecular imaging strategies that can specifically interrogate different epigenetic mechanisms in vivo. The main goal of this proposal is to develop novel in vivo imaging strategies to monitor cellular epigenetic processes in living animals, evaluating these techniques when imaging the basic epigenetic shifts occurring in the development of different cancers, and to apply these imaging platforms to study therapeutic drugs that modulate these processes in cancer. Specifically, we wish to image and quantitate histone methylation in vivo, and to apply this novel analytical tool to evaluate drugs that modulate histone methylation, which may have important applications in molecular therapeutics of cancer. This will be achieved by developing: 1) Optical bioluminescence (Split-Luciferase-complementation), and 2) microPET (Split-Thymidine kinase complementation) imaging sensors. Combinatorial therapies using different epigenetic modulators (inhibitors of histone deacetylases in combination with histone methyltransferases) is curently considered as a new approach for treating cancers and several other intractable cellular diseases. The sensors we are planning to develop by this grant, are having the potential to image molecular events in both cells and in live animals. These sensors will improve the use of epigenetic modulators in translational clinical applications by enabling drug screening and their pre-clinical evaluations in living animals. The aberrant histone methylation has been considered as an important player in the development of cancer. In summary, this proposal will lead to the development of highly sensitive in vivo imaging methods that can be used to further epigenetic research, as well as accelerating the pre-clinical evaluation of drugs targeting different cancers and other cellular diseases.
Currently, abnormal epigenetic mechanisms are regarded as significant contributing factors to the pathophysiology of different diseases, including cancer. Several cell-based assays are being used to identify and analyze drugs that target different epigenetic mechanisms. However most of these tests are not capable of predicting the exact behavior of drug pharmacokinetics and pharmacodynamics in living subjects. The ever- increasing interest in epigenetics research creates an immediate need to develop new more meaningful molecular imaging strategies that can specifically interrogate different epigenetic mechanisms in vivo. The main goal of this proposal is to develop novel in vivo imaging strategies to monitor cellular epigenetic processes in living animals. Specifically, we wish to image and quantitate histone methylation in vivo, and to apply this novel analytical tool to the evaluation of drugs that modulate epigenetic events, which may have important applications in molecular therapeutics of cancer.
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