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Molecular Imaging of Protein Kinase Activity and Their Application in Diseases. Diseases.
[摘要] Protein kinases are important regulators of signaling pathways. Dysregulation of protein kinases can be triggered by a variety of stimuli (such as environmental toxins) and is associated with a number of human disorders. Developing tools which allow real time, non-invasive, dynamic and quantitative imaging of kinase activity will facilitate a better understanding of biological processes in the cellular and molecular levels and provide a solid foundation for rational kinase inhibitor design. In this work, a new reporter platform based on complementation of firefly luciferase was described for monitoring kinase (Akt and Met) activity in living subjects.The Ser/Thr kinase Akt mediates mitogenic and anti-apoptotic sequelae that result from activation of multiple signaling cascades. The Akt pathway is considered as a key determinant of biologic aggressiveness of tumors. Using bioluminescent Akt reporter, Akt activity in cultured cells and in tumor xenografts was monitored quantitatively and dynamically in response to receptor tyrosine kinase activation or inhibition, as well as direct inhibition of Akt. A bioluminescent reporter based on the same platform was also generated to study receptor tyrosine kinase Met. Met/HGF pathway modulates signaling cascades implicated in normal cellular activities that are root of cancer cell dysregulation. Using bioluminescent Met reporter, Met activity in response to the inhibition of the HGF/Met signaling pathway was studied in a glioma model. To monitor protein kinase activity in the tissue dependent manner, a Cre-mediated transgenic mouse model expressing bioluminescent Akt reporter was generated wherein Akt kinase activity can be monitored non-invasively in the cells and tissues that have undergone Cre-mediated recombination.Results obtained from these studies provided unique insights into the pharmacokinetics and pharmacodynamics of agents that modulate kinase activity, allowed development of optimal dosing and schedule parameters for maximal tumor control in cancer treatment, and validated protein kinase as a target for brain cancer therapy. This work demonstrates that bioluminescence reporter assays provided novel methodologies to study protein kinases. Such assays will greatly aid in the characterization of molecular events in mammalian cells, enable the screening of compounds which inhibit kinase activation and pave the way for discovery of novel clinical therapies.
[发布日期]  [发布机构] University of Michigan
[效力级别] Science [学科分类] 
[关键词] Molecular Imaging of Protein Kinase Activity;Science;Toxicology [时效性] 
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