We propose to establish a Biomedical Technology Research Center (BTRC) in High Performance Computing for Multiscale Modeling of Biological Systems, as a joint effort between the U of Pittsburgh (Pitt;lead institution), Carnegie Mellon U (CMU), the Pittsburgh Supercomputing Center (PSC) and Salk Institute. The Center will develop technology and tools to facilitate research and training at the interface between computing technology and life sciences, and focus on a deeper understanding ofthe molecular and cellular organization and mechanisms that underlie synaptic signaling and regulation, thus facilitating the discovery of new treatments against nervous system disorders. The goal is to start filling the gap between modeling efforts at disparate scales of structural biology, cellular microphysiology and large scale image analysis. Computational technology research and development (TR&D) studies will be conducted in (i) molecular modeling and simulations, (ii) cell modeling and simulations, and (iii) bioimage processing and analysis. These activities will emphasize developing tools to tackle the spatial and molecular complexity inherent in signal transmission and will be driven by five experimental driving biomedical projects (at Pitt, Caltech, Harvard and UT Southwestern Medical Center) on (i) neurotransmitter transport by excitatory amino acid transporters, (ii) activation of CaMKII in spines, (iii) dopamine transporter trafficking in dopamie neurons, (iv) Itk as a regulator of T cell signaling, and (iv) neuronal circuit reconstruction from serial section transmission electron microscopy images. The Center will carry out a vigorous training and dissemination program in its areas of concentration, it will leverage the capabilities of the PSC which has been home to a BTRC for more than twenty years and, besides its biomedical technology research, has a long track record of service, training and dissemination. It will also take advantage ofthe unique strengths ofthe Computational &Systems Biology Department at Pitt, and the Lane Center for Computational Biology at CMU, building on numerous successful collaborative research and training efforts between the two universities, and cutting-edge research at the Computational Neurobiology Laboratory at the Salk Institute.

Public Health Relevance

This project will develop powerful computational tools for analyzing and relating observations of neural systems and the brain at scales varying from molecular to cellular to tissue. These, will provide insights into mechanisms that distinguish normal from defective proteins, cells or organisms. These results will help accelerate the discovery of new pharmacological approaches for treating nervous system diseases associated with signaling disorders

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Biotechnology Resource Grants (P41)
Project #
1P41GM103712-01
Application #
8414647
Study Section
Special Emphasis Panel (ZRG1-BST-N (40))
Program Officer
Swain, Amy L
Project Start
2012-09-24
Project End
2017-07-31
Budget Start
2012-09-24
Budget End
2013-07-31
Support Year
1
Fiscal Year
2012
Total Cost
$1,578,900
Indirect Cost
$189,359
Name
University of Pittsburgh
Department
Biology
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Ma, Shiqi; Cheng, Mary H; Guthrie, Daryl A et al. (2017) Targeting of dopamine transporter to filopodia requires an outward-facing conformation of the transporter. Sci Rep 7:5399
Morel, Penelope A; Lee, Robin E C; Faeder, James R (2017) Demystifying the cytokine network: Mathematical models point the way. Cytokine 98:115-123
Huang, Yu-Ming M; Raymundo, Mark Anthony V; Chen, Wei et al. (2017) Mechanism of the Association Pathways for a Pair of Fast and Slow Binding Ligands of HIV-1 Protease. Biochemistry 56:1311-1323
Gretzmeier, Christine; Eiselein, Sven; Johnson, Gregory R et al. (2017) Degradation of protein translation machinery by amino acid starvation-induced macroautophagy. Autophagy 13:1064-1075
Sauerwald, Natalie; Zhang, She; Kingsford, Carl et al. (2017) Chromosomal dynamics predicted by an elastic network model explains genome-wide accessibility and long-range couplings. Nucleic Acids Res 45:3663-3673
Rouviere, Eric; Arnarez, Clément; Yang, Lewen et al. (2017) Identification of Two New Cholesterol Interaction Sites on the A2A Adenosine Receptor. Biophys J 113:2415-2424
Cheng, Mary Hongying; Garcia-Olivares, Jennie; Wasserman, Steven et al. (2017) Allosteric modulation of human dopamine transporter activity under conditions promoting its dimerization. J Biol Chem 292:12471-12482
Mikulska-Ruminska, K; Kulik, A J; Benadiba, C et al. (2017) Nanomechanics of multidomain neuronal cell adhesion protein contactin revealed by single molecule AFM and SMD. Sci Rep 7:8852
Li, Hongchun; Sharma, Nanaocha; General, Ignacio J et al. (2017) Dynamic Modulation of Binding Affinity as a Mechanism for Regulating Interferon Signaling. J Mol Biol 429:2571-2589
Ruan, Xiongtao; Wülfing, Christoph; Murphy, Robert F (2017) Image-based spatiotemporal causality inference for protein signaling networks. Bioinformatics 33:i217-i224

Showing the most recent 10 out of 147 publications