This application seeks competitive renewal of the NIGMS-supported New Mexico Center for the Spatiotemporal Modeling of Cell Signaling (Spatiotemporal Modeling Center;STMC). Our Center focuses remarkable strengths in biology, technology, modeling and simulation on understanding how the spatial proximity, dynamics, interactions and trafficking of membrane receptors and signaling proteins together determine the outcome of signal transduction networks. Research foci include the ITAM family of immunoreceptors, particularly the high affinity IgE receptor (Fc?RI) that is responsible for triggering both the symptoms and progression of allergic inflammation. The innate immune receptor, Dectin-1, bears a truncated """"""""hemITAM"""""""" and its novel signaling control will be studied in detail over the renewal period. STMC researchers also specialize in the EGFR and other receptor tyrosine kinases. A major focus in this proposal is the unusual cross-talk between EGFR/erbB receptors and the Met/Ron family - and their complex control of carcinogenesis and metastasis. The experimental teams will quantify the distributions, mobility, interactions and post-translational modifications of receptors and adaptors that mediate both signaling and trafficking after exposure to ligand. Each research project is highly integrated with respect to experimental and mathematical modeling components. Computational specialists in the STMC's Modeling and Bioinformatics Core include pioneers in the field of rule-based modeling approaches, which are applied to develop mechanistic kinetic models and to implement powerful spatial stochastic platforms that consider the contribution of the membrane landscape to receptor signaling. In vivo and in silico tumor models will provide insights into the mechanisms by which the erbB and Met receptors control responses to targeted therapies. Multiple new technologies will be deployed within the projects, including real-time confocal and hyper-spectral microscopy with quantum dot- tagged ligands to track receptor distributions and interactions in live cells, novel TIRF imaging assays on live cells, photo-bleaching protocols that quantify protein-protein reaction kinetics, and novel microfluidic devices to image events in rare primary cells and quantify the release of mediators. The STMC community is supported by strong cores. The STMC Super-resolution and Image Analysis Core provides new instrumentation and probes to access protein-protein dynamics at the 10 nm scale and is dedicated to the improved analysis and cross-platform integration of image data, as well as the archiving and sharing of both image and biochemical data, and the broad dissemination of data, code and models. The STMC Training and Outreach Core provides exceptional opportunities for young biomedical, mathematical, statistical, physical and computational scientists, as well as engineers and physicians, to build exciting and productive careers with potential to impact human health. The STMC Administration Core maximizes the ability of center members to conduct innovative science and will continue to support our aspiration to serve as a national model for diversity in Systems Biology through the continued recruitment and advancement of women and minorities.

Public Health Relevance

The New Mexico Center for Spatiotemporal Modeling unites an interdisciplinary group of experimentalists, computational biologists and engineers to focus on the mechanisms of cellular signal transduction. Our model systems represent important problems in immunology, such as the methods by which allergens trigger release of inflammatory mediators. In the field of cancer, we focus on receptors that control cancers of the colon and ovary. We specifically seek insight into the ways that these cancers escape current targeted therapies, which should led to better drug combinations.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Specialized Center (P50)
Project #
2P50GM085273-06
Application #
8767019
Study Section
Special Emphasis Panel (ZGM1)
Program Officer
Dunsmore, Sarah
Project Start
2008-07-01
Project End
2019-07-31
Budget Start
2014-09-01
Budget End
2015-07-31
Support Year
6
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of New Mexico Health Sciences Center
Department
Pathology
Type
Schools of Medicine
DUNS #
City
Albuquerque
State
NM
Country
United States
Zip Code
87131
Termini, Christina M; Gillette, Jennifer M (2017) Tetraspanins Function as Regulators of Cellular Signaling. Front Cell Dev Biol 5:34
Harmon, Brooke; Chylek, Lily A; Liu, Yanli et al. (2017) Timescale Separation of Positive and Negative Signaling Creates History-Dependent Responses to IgE Receptor Stimulation. Sci Rep 7:15586
Schwartz, Samantha L; Cleyrat, Cédric; Olah, Mark J et al. (2017) Differential mast cell outcomes are sensitive to Fc?RI-Syk binding kinetics. Mol Biol Cell 28:3397-3414
Kocha?czyk, Marek; Kocieniewski, Pawe?; Koz?owska, Emilia et al. (2017) Relaxation oscillations and hierarchy of feedbacks in MAPK signaling. Sci Rep 7:38244
Mrass, Paulus; Oruganti, Sreenivasa Rao; Fricke, G Matthew et al. (2017) ROCK regulates the intermittent mode of interstitial T cell migration in inflamed lungs. Nat Commun 8:1010
Medina, Christopher S; Manifold-Wheeler, Brett; Gonzales, Aaron et al. (2017) Automated Computational Processing of 3-D MR Images of Mouse Brain for Phenotyping of Living Animals. Curr Protoc Mol Biol 119:29A.5.1-29A.5.38
Graus, Matthew S; Neumann, Aaron K; Timlin, Jerilyn A (2017) Hyperspectral fluorescence microscopy detects autofluorescent factors that can be exploited as a diagnostic method for Candida species differentiation. J Biomed Opt 22:16002
Mahajan, Avanika; Youssef, Lama A; Cleyrat, Cédric et al. (2017) Allergen Valency, Dose, and Fc?RI Occupancy Set Thresholds for Secretory Responses to Pen a 1 and Motivate Design of Hypoallergens. J Immunol 198:1034-1046
Freed, Daniel M; Bessman, Nicholas J; Kiyatkin, Anatoly et al. (2017) EGFR Ligands Differentially Stabilize Receptor Dimers to Specify Signaling Kinetics. Cell 171:683-695.e18
Cleyrat, Cédric; Girard, Romain; Choi, Eun H et al. (2017) Gene editing rescue of a novel MPL mutant associated with congenital amegakaryocytic thrombocytopenia. Blood Adv 1:1815-1826

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