Notch signaling is an evolutionary conserved mechanism used by metazoans to direct cell fatedecisions, proliferation and apoptosis at all stages of development, including self-renewing adult tissues.Aberrant Notch signaling is implicated in cancer, especially in the emerging field of cancer stem cells.Mammalian cells contain four Notch receptors and five Delta and Jagged cognate ligands; the overall goal ofthis proposal is to elucidate the significance of context on individual Notch receptor subtype-mediated signalsusing non-invasive molecular imaging strategies. We propose to develop enabling technologies that willfacilitate high throughput screening for agents and gene products that are capable of modulating the Notchsignaling pathway in cancer, inherited diseases and facilitate tissue engineering. A comprehensivemechanistic understanding of how to manipulate individual receptors in a context-dependent manner stilleludes investigators. We propose to develop a real time imaging system that will go beyond the currentlyavailable reporters in providing real time, quantitative accounting of the activation status of individual Notchreceptor subtypes. The reporter system we are developing is based on the luciferase complementationimaging technology developed in the ICMIC Molecular Reporter Core at Washington University School ofMedicine and enables visualization of the interactions between a specific Notch intracellular domain (NICD)and the common nuclear cofactor RBPjk. The system is versatile; it can be adaptedfor studying the pathwayin different cell types and can be easily modified to monitor interaction with other cancer-relevant partnerssuch as components of the NF-kB pathway. While the imaging technology being developed in thisapplication is not directly applicable to imaging in patients as it requires protein engineering, thesemethodologies will help develop and evaluate novel therapies for Notch-related diseases.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
2P50CA094056-07
Application #
7287030
Study Section
Special Emphasis Panel (ZCA1-SRRB-9 (J1))
Project Start
2007-09-28
Project End
2011-12-11
Budget Start
2007-09-28
Budget End
2007-12-31
Support Year
7
Fiscal Year
2007
Total Cost
$245,723
Indirect Cost
Name
Washington University
Department
Type
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Miller, Jessica; Wang, Steven T; Orukari, Inema et al. (2018) Perfusion-based fluorescence imaging method delineates diverse organs and identifies multifocal tumors using generic near-infrared molecular probes. J Biophotonics 11:e201700232
Zacharias, Niki; Lee, Jaehyuk; Ramachandran, Sumankalai et al. (2018) Androgen Receptor Signaling in Castration-Resistant Prostate Cancer Alters Hyperpolarized Pyruvate to Lactate Conversion and Lactate Levels In Vivo. Mol Imaging Biol :
Cherian, Mathew A; Olson, Sydney; Sundaramoorthi, Hemalatha et al. (2018) An activating mutation of interferon regulatory factor 4 (IRF4) in adult T-cell leukemia. J Biol Chem 293:6844-6858
Hövener, Jan-Bernd; Pravdivtsev, Andrey N; Kidd, Bryce et al. (2018) Parahydrogen-Based Hyperpolarization for Biomedicine. Angew Chem Int Ed Engl 57:11140-11162
Bauerle, Kevin T; Hutson, Irina; Scheller, Erica L et al. (2018) Glucocorticoid Receptor Signaling Is Not Required for In Vivo Adipogenesis. Endocrinology 159:2050-2061
Prudner, Bethany Cheree; Sun, Fangdi; Kremer, Jeffrey Charles et al. (2018) Amino Acid Uptake Measured by [18F]AFETP Increases in Response to Arginine Starvation in ASS1-Deficient Sarcomas. Theranostics 8:2107-2116
Meinerz, Kelsey; Beeman, Scott C; Duan, Chong et al. (2018) Bayesian Modeling of NMR Data: Quantifying Longitudinal Relaxation in Vivo, and in Vitro with a Tissue-Water-Relaxation Mimic (Crosslinked Bovine Serum Albumin). Appl Magn Reson 49:3-24
Zheleznyak, Alexander; Shokeen, Monica; Achilefu, Samuel (2018) Nanotherapeutics for multiple myeloma. Wiley Interdiscip Rev Nanomed Nanobiotechnol 10:e1526
Choi, Jaebok; Cooper, Matthew L; Staser, Karl et al. (2018) Baricitinib-induced blockade of interferon gamma receptor and interleukin-6 receptor for the prevention and treatment of graft-versus-host disease. Leukemia 32:2483-2494
Kotagiri, Nalinikanth; Cooper, Matthew L; Rettig, Michael et al. (2018) Radionuclides transform chemotherapeutics into phototherapeutics for precise treatment of disseminated cancer. Nat Commun 9:275

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