Driving Biomedical Projects

MMBioS Driving Biomedical Projects (DBPs)

DBPs consist of two categories:

  • 7 DBPs in progress
    • 3 newly added (DBPs 6-8, highlighted in yellow)
    • 4 continuing from previous term (DBPs 1-4)
  • 1 completed DB (DBP5;shaded in gray).

 

DBP number and title(a) Primary Collaborators (PIs)

TR&D projects

BTRR Leader(s) and personnel

How the DBP acts as a driver of test bed?

External Funding Status

(Grant #, title, source and start and end dates if applicable)

Pubs(b)

1.Dynamics of Neurotransmitter Transporters: Molecular and Cellular Interactions

Susan Amara, NIH

Gonzalo Torres, U of Florida

1, 2, 3,4

Bahar

Cheng, Liu, Faeder, Sejnowski, Bartol

Site-directed mutagenesis, sulfhydryl modification, and chemical cross-linking approaches and biochemical and elctro-physiological analyses of EAAT3 provide data for building, teseting and refining computational models for anion channeling.

Experiments with cell permeable peptide fragments and DAT mutagenesis, in brain synaptosomes and in vivo drive the computational modeling of DAT - G protein βγ complex.

 

Data on PKA- and RhoA-dependent signaling events and TAAR1 activation will drive the development and benchmarking of BioNetGen model for identifying pathways/targets that involved in AMPH action on DAT.

1ZIAMH002946-03,Structure, function and pharmacology of neurotransmitter reuptake systems (Amara)

7R01 DA038598 Regulation of dopamine transporter function by G protein β−γ subunits (Torres); 9/15/14 - 6/30/19

-

2.Regulation and binding to PSD- 95 and its relation to AMPA receptor trafficking

Mary Kennedy, Caltech

 

2, 3, 1

 

Sejnowski Bartol, Wetzel, Hood, Bahar, Faeder

This project will drive development of the spatial extensions to BioNetGen Language (BNGL) for MCell in two ways, by enabling MCell to deal with combinatorial complexity of the multiple interactions of PDZ domain, and by allowing to including trans-synaptic interactions

5R01MH095095-04, Time resolved assay of synaptic enzyme activity by mass spectrometry; 7/1/11- 4/30/16 (Kennedy)

Caltech Institutional Funds (Kennedy)

1,2,3

3. Multiscale modeling of DAT function in dopamine neurons

Alexander Sorkin,
Pitt

Gonzalo Torres, U of Florida

1, 2, 3, 4

Bahar, Faeder

Cheng, Liu Sejnowski, Bartol, Murphy

Super-resolution time-dependent image data on DA neurons (obtained by EM, immunogold labeling and fluorescence microscopy) using

transgenic knock-in mouse model (with HA- tagged DAT) will drive the construction of a spatiotemporally realistic model and MCell simulations of DA reuptake and the effects of drugs/psychostimulants and DA reuptake (influx) or reverse transport (efflux) that will be validated against experiments.

5R01DA014204-14, Dopamine transporter regulation by endocytosis ; 4/1/01-4/30/17

(Sorkin)

7R01DA038598, Regulation of dopamine transporter function by G protein β−γ subunits (Torres); 9/15/14 - 6/30/19

4

4. Spatiotemporal modeling of T cell signaling

Christoph Wuelfin, Bristol (UK)

Peter Cullen

Paul Verkade

3, 4

 

Murphy

Ramanan, Faeder

The project is essential to the creation of CellOrganizer functions for aligning and comparing spatiotemporal distributions of multiple molecules and creating causal models

ERC PCIG11-GA-2012-321554, The spatiotemporal organization of T cell signaling as a regulator of T cell function, European Research Council (Wülfing), 8/1/12-7/31/16

102387/Z/13/Z, Characterising the disruption of signalling dynamics at the immune synapse interface of tumour infiltrating lymphocytes, Wellcome Trust (Wülfing), 8/1/14- 9/30/17

201254/Z/16/Z, Ability of Tumour Infiltrating Lymphocytes (TILs) to Mediate Tumour Killing, Wellcome Trust (Wülfing), 5/1/16-4/30/19

GW4 BioMed DTP, Defining Mechanisms of T Cell Suppression in the Tumour Microenvironment, Medical Research Council (Wülfing), 9/1/16-8/31/19

5,6,10*

5. Functional connectomics

Clay Reid, Allen Brain Institute

 

4

Wetzel

Hood

This project has driven the development of our image alignment software to register and analyze image stacks of 10 to 100 terabytes comprising millions of raw images, and successfully resulted in the publication of the largest-to-date (to our knowledge) network of cortical neurons in Nature 2016.

5R01NS075436-05, Large-scale connectivity and function in a cortical circuit; 6/15/11-4/30/16 (Reid)

7,11

6. Constructing a dynamic, spatial map of transcription and chromatin structure

Daniel Larson, NIH

1, 4

Kingsford

Murphy, Bahar

The DBP will drive (i) the extension of protein structure and dynamics analysis software such as ProDy to chromo-some- scale modeling using imaging-derived contact maps and (ii) the development of probabilistic spatial models from movies of one or more image fluorescent spots, from which to derive contact maps and other spatial measurements.

1ZIABC011383-05, Transcription and splicing dynamics in single cells, NCI Div Basic Sci (Larson)

-

7. Structure and function of synapses

Kristen Harris, UT Austin

2, 3

Sejnowski, Bartol, Faeder, Wetzel, Hood

Content-rich data from EM tomography, serial section EM imaging and analysis will be used to construct spatiotemporally realistic models for neuronal dendrites, axons and synapses, and subcellular components such as ER, mitochondria and endosomes and simulate synaptic function and LTP.

5R01MH104319-02, Synapse growth and elimination in mature CNS (Harris) 9/26/2014 - 6/30/2019

5R01NS074644-22, Distance- dependent structure and function of neuronal dendrites (Harris) 9/30/97-12/31/16

1,2,8,9

8. Scalable approaches to modeling using large sets of rules and images

Peter Sorger, Harvard

3, 4

Faeder,

Murphy

This DBP will drive the development of integrated tools for model development visualization, calibration, and analysis that are much needed for any modeling project, and the improvement of generative modeling tools that capture biophysical relationships independent of the details of image acquisition and can be used in conjunction with model calibration to study mechanism

U54-HL127365-02: Pharmaco- response signatures and disease mechanism (LINCS); (Sorger) 9/10/14-6/30/20

DARPA W911NF-14-1-0397 Programmatic modeling for reasoning across complex mechanisms (Sorger)

 

(a) the row shaded in gray refers to completed DBP
(b) Publication numbers refer to the list below. Ref 7 was published prior to the start date of the award; Ref 10 is in press.

 

Publications that resulted from the DBPs:

 

  1. Bartol TM, Keller DX, Kinney JP, Bajaj CL, Harris KM, Sejnowski TJ, Kennedy MB (2015) Computational reconstitution of spine calcium transients from individual proteins Front Synaptic Neurosci 7: 17 PMID: 26500546, PMC4595661
  2. Bartol TM, Keller DX, Kinney JP, Bajaj CL, Harris KM, Sejnowski TJ, Kennedy MB (2015) Nanoconnectomic upper bound in the variability of synaptic plasticity Elife 4.pii: e10778 PMID: 26618907, PMC4737657

  3. Stefan MI, Bartol TM, Sejnowski TJ, Kennedy MB (2014) Multi-state modeling of biomolecules PLoS Comp Biol 10(9):e1003844. PMID: 25254957, PMC4201162

  4. Cheng MH, Block E, Hu F, Cobanoglu MC, Sorkin A, Bahar I (2015) Insights into the modulation of dopamine transporter function by amphetamine, orphenadrine, and cocaine binding Front Neurol 6: 134 PMID: 26106364, PMC4460958
  5. Roybal KT, Sinai P, Verkade P, Murphy RF, Wuelfing C (2013) The actin-driven spatiotemporal organization of T-cell signaling at the system scale Immunol Rev 256: 133-47 PMID: 24117818.
  6. Roybal*, K.T.; T. E. Buck*, X. Ruan*, B. H. Cho, D. J. Clark, R. Ambler, H. M. Tunbridge, J. Zhang, P. Verkade, C. Wuelfing, and R. F. Murphy (2016) Computational spatiotemporal analysis identifies WAVE2 and Cofilin as joint regulators of costimulation-mediated T cell actin dynamics. Science Signaling 9: rs3 [*co-first authors].
  7. Bock DD, Lee WC, Kerlin AM, Andermann ML, Hood G, Wetzel AW, Yurgenson S, Soucy ER, Kim HS, Reid RC (2011) Network anatomy in vivo physiology of visual cortical neurons Nature 471: 177-82 PMID: 21390124, PMC3095821
  8. Edwards J, Daniel E, Kinney J, Bartol T, Sejnowski T, Johnston D, Harris K, Bajaj C (2014) VolRoverN: enhancing surface and volumetric reconstruction for realistic dynamical simulation of cellular and subcellular function Neuroinformatics 12:277-89 PMID: 24100964, PMC4033674
  9. Kinney JP, Spacek J, Bartol TM, Bajaj CL, Harris KM, Sejnowski TJ (2013) Extracellular sheets and tunnels modulate glutamate diffusion in hippocampal neuopil J Comp Neurol 521: 448-64 PMID: 22740128, PMC3540825
  10. Ambler*, JE, X. Ruan*, R. F. Murphy, and C. Wülfing(2016) Systems Imaging of the Immune Synapse. Methods in Molecular Biology, in press [*co-first authors, co-senior authors].
  11. Lee, W. A.; Bonin, V.; Reed, M.; Graham, B. J.; Hood, G.; Glattfelder, K.; Reid, R. C (2016) Anatomy and function of an excitatory network in the visual cortex. Nature 532: 370-374 PMID: 27018655, PMC4844839

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