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 #
5P41GM103712-02
Application #
8549842
Study Section
Special Emphasis Panel (ZRG1-BST-N (40))
Program Officer
Ravichandran, Veerasamy
Project Start
2012-09-24
Project End
2017-07-31
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
2
Fiscal Year
2013
Total Cost
$2,393,898
Indirect Cost
$205,543
Name
University of Pittsburgh
Department
Biology
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Sparks, Samuel; Temel, Deniz B; Rout, Michael P et al. (2018) Deciphering the ""Fuzzy"" Interaction of FG Nucleoporins and Transport Factors Using Small-Angle Neutron Scattering. Structure 26:477-484.e4
Donovan-Maiye, Rory M; Langmead, Christopher J; Zuckerman, Daniel M (2018) Systematic Testing of Belief-Propagation Estimates for Absolute Free Energies in Atomistic Peptides and Proteins. J Chem Theory Comput 14:426-443
Li, Jing; Ostmeyer, Jared; Cuello, Luis G et al. (2018) Rapid constriction of the selectivity filter underlies C-type inactivation in the KcsA potassium channel. J Gen Physiol 150:1408-1420
Gupta, Sanjana; Hainsworth, Liam; Hogg, Justin S et al. (2018) Evaluation of Parallel Tempering to Accelerate Bayesian Parameter Estimation in Systems Biology. Proc Euromicro Int Conf Parallel Distrib Netw Based Process 2018:690-697
Ponzoni, Luca; Zhang, She; Cheng, Mary Hongying et al. (2018) Shared dynamics of LeuT superfamily members and allosteric differentiation by structural irregularities and multimerization. Philos Trans R Soc Lond B Biol Sci 373:
Ruiz-Martínez, Álvaro; Bartol, Thomas M; Sejnowski, Terrence J et al. (2018) Efficient models of polymerization applied to FtsZ ring assembly in Escherichia coli. Proc Natl Acad Sci U S A 115:4933-4938
Krieger, James; Lee, Ji Young; Greger, Ingo H et al. (2018) Activation and desensitization of ionotropic glutamate receptors by selectively triggering pre-existing motions. Neurosci Lett :
Bromer, Cailey; Bartol, Thomas M; Bowden, Jared B et al. (2018) Long-term potentiation expands information content of hippocampal dentate gyrus synapses. Proc Natl Acad Sci U S A 115:E2410-E2418
Spealman, Pieter; Naik, Armaghan W; May, Gemma E et al. (2018) Conserved non-AUG uORFs revealed by a novel regression analysis of ribosome profiling data. Genome Res 28:214-222
Debiec, Karl T; Whitley, Matthew J; Koharudin, Leonardus M I et al. (2018) Integrating NMR, SAXS, and Atomistic Simulations: Structure and Dynamics of a Two-Domain Protein. Biophys J 114:839-855

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