| Service projects are established through the use of NBCR compute resources, software tools and databases, and require support from NBCR to ensure the goals are met. Service projects may become Collaborative projects, which are drivers for scientific and technology development, and vice versa. Through service projects, the impact of NBCR as a national center is further broadened. Lead investigators of service projects typically have independent funding besides scientific consultation & technological assistance from NBCR. The following are selected examples to illustrate the broad range of possibilities. Please see the Software tools for relevance to your projects, and contact the investigators about accessing services provided by NBCR. |
|
Investigators and Affiliation(s) |
Grant agency, number and title |
Description and use of NBCR tools |
|
Quantum to Continuum Mechanics Tools |
|
Thanh Truong
University of Utah |
NSF CTS 0112306
Virtual Kinetic Laboratory |
This work involves extensions of tools
and expertise developed within NBCR to include
thermodynamics and chemical kinetics capabilities that
have been developed in the Truong lab. In particular the
extensions of the portals, new database tools,
and visualization capabilities developed in NBCR,
merging of GAMESS with the thermodynamic and
chemical kinetics software, and the production of
associated educational materials. |
|
Avigdor Scherz
Weizmann Institute of Science |
United States - Israel Binational Science
Foundation BSF-59656A
An Experimental Look into
Sub-Electron Charge Flow |
In this work, we use our computational
chemistry software (GAMESS and QMView) and
expertise of NBCR to understand that the charge
flow of a fraction of electron between a chelated metal
center and reversibly bound molecules can be accurately
monitored experimentally and used as a benchmark for
various computational and theoretical approaches. |
|
Jose Onuchic
University of California San Diego |
NSF PHY 0216576
Center for Theoretical
Biological Physics |
The CTBP will pioneer new approaches to
this problem, by coupling molecular dynamics simulators
(such as CHARMM and AMBER) to Poisson-Boltzmann solvers
that provide an implicit treatment of solvent dynamics.
Our target problem is the functional motions of the
ribosome, as there is a significant amount of experimental
information regarding this critical biological system. We
will use codes developed by NBCR, such as the Adaptive
Poisson-Boltzmann Solver and the Adaptive
Smoluchowski Equation Solver and the cluster resources
to gain insight into this system. |
|
Data Analysis Tools for Molecular
Sequences |
|
Michael Fromm (PI)
University of Nebraska, Lincoln |
National Science Foundation DBI-9975808
A Protein Interaction Map
for Rice Kinases |
Although the model organism used here
is Rice, the primary focus of this work is on elucidating
the mechanism of signal transduction. This is of high
relevance and importance to biomedical research because of
the importance of signal transduction processes in human
biology and disease (especially in neoplsia). The
algorithms, software, and databases developed in this
project and made available in MIA and Homophila are
equally applicable to projects that are more closely tied
to traditional NIH model systems and their propagation to
these systems will be expedited by NBCR. |
|
Steven Henikoff (PI)
Fred Hutchinson Cancer Research Institute |
NIGMS 5R01GM029009
Alignment Based Methods for
Molecular Sequence Analysis |
With the advent of Motif Alignment and
Search Tool (MAST) , we have been able to link
Block Searcher and Block Maker to MAST so that users can
search selected blocks from the Blocks or their own blocks
made by Block Maker against the major sequence databases.
This has enhanced the utility of the Blocks Web Server
(http://blocks.fhcrc.org/) considerably. |
| Heart Modeling |
|
CARDIAC ARRHYTHMIA |
|
Jack M. Rogers, PhD (PI)
Assistant Professor of Biomedical
Engineering, University of Alabama at Birmingham
|
NIH NHLBI
HL 64184 Mechanisms for Maintenance of
Ventricular Fibrillation |
We have used Continuity as a testbed for a new model of the cardiac action
potential (Rogers, 2000) and in combination with the model
of rabbit ventricular geometry to predict the effects of
heterogeneous Gaussian curvature on cardiac wavefronts
(Rogers, 2002). High speed computational models of
ventricular and atrial fibrillation that respond to pacing
stimuli will enable us to screen pacing strategies for
arrhythmia control before testing them in animal
preparations. |
|
Andrew Pollard, PhD (PI)
Professor of Biomedical Engineering,
University of Alabama at Birmingham
Raymond Ideker, MD (Program PI)
Professor,
Cardiac Rhythm Management Laboratory,
University of Alabama at Birmingham |
NIH NHLBI P01 HL67961
Mechanisms and therapy of ischemic sudden
cardiac arrest. (Ideker, Program PI) Project 3.
Purkinje-myocardial reentry in ischemia and infarction. |
We have used the epicardial rabbit mesh
derived from the NBCR rabbit model to study responses to
anti-tachycardia pacing pulses replicating burst pacing
schemes from standard devices. The main goal of the
present studies is to establish the efficacy of burst
pacing with a second ventricular lead. To investigate the
role of the Purkinje systems in reentrant rhythms during
myocardial ischemia and infarction, the development by
NBCR investigators of canine and rabbit ventricular models
with Purkinje fibers will be valuable for this goal. |
|
NSF GOALI grant BES-9903466
Model and experimental studies of the
evolution of the excitable gap for improved anti-tachcardia
pacing |
|
Sanjiv M. Narayan, MD, PhD (PI) Assistant
Professor of Medicine (Cardiology),
UCSD
Director of Electrophysiology, VA San
Diego |
AHA Western States Affiliates
Grant-in-aid 0265120Y
Regional Ventricular Strain,
Repolarization Anisotropy and Arrhythmogenesis
|
This project is designed to address the
contribution of mechanoelectric feedback to the initiation
of ventricular arrhythmias during passive ventricular
dilatation. We are testing the hypothesis that non-uniform
ventricular wall strain alters tissue electrophysiology
and leads to arrhythmogenesis by optically imaging
Langendorff-perfused rabbit heart. Continuity and the cardiac data analysis tools of the NBCR are
also being used to analyze impulse propagation and
regional strain patterns imaged simultaneously in isolated
rabbit hearts to investigate the role of mechanical
heterogeneity on dispersion of repolarization and
arrhythmogenesis. New work will extend the analysis to
failing rabbit hearts, which are studied in vivo by
rapid endoventricular pacing. |
|
NIH NHLBI
5 K23 HL70529-02
The Pathophysiology of T-Wave Alternans
|
This project
is designed to study the dynamics of T-wave alternans (TWA)
on the surface ECG and associated endoventricular
monophasic action potentials to better understand
repolarization dynamics at the initiation of ventricular
tachyarrhythmias in patients at risk for sudden death. The
realistic fiber orientation and ventricular geometry of
the Continuity models will allow the
contribution of anisotropic conduction and electrotonic
modulation on TWA to be quantitatively assessed. We will
also explore the effects of systematic subtle alterations
in modeled ion channel function on alternans and
arrhythmogenesis. |
|
Igor Efimov, PhD (PI)
Associate Professor of Biomedical
Engineering,
Case Western Reserve University |
NIH/NHLBI R01HL67322
Virtual electrode hypothesis of
defibrillation
R01HL58808
Structure / function of the AV node |
The long term goals of my research
projects, funded by NIH are related to: (1) shock-induced
arrhythmogenesis, (2) electric-field induced
electroporation, (3) the role of structure of the
supravetricular conduction system of the heart in its
electrophysiological function. All goals rely on
mathematical modeling of the cellular and tissue
electrophysiology. In particular, our defibrillation
project has significantly benefited from the NBCR model
of the rabbit heart, which permitted us to develop an
anatomically detailed model of ventricular defibrillation. |
|
CARDIAC SURGERY |
|
D. Craig Miller, MD (PI)
Thelma and Henry Doelger Professor of
Cardiovascular Surgery,
Stanford University School of Medicine
Neil B. Ingels, Jr., PhD (Co-PI)
Head, Laboratory of Cardiovascular
Physiology and Biophysics, Research Institute, Palo Alto
Medical Foundation |
NIH NHLBI
1 RO1 HL29589 Ventricular Dynamics from
Surgically Inserted Markers
|
This project use radiopaque markers in
ovine experimental models to test hypotheses concerning
the mechanisms for left ventricular (LV) remodeling
leading to congestive heart failure and/or chronic
ischemic mitral regurgitation. In addition to our standard
LV and valvular marker arrays, we have added LV transmural
beadsets for simultaneous measurement of 4-D biomechanics
of myofiber sheets and extracellular matrix. Continuity is used to compute non-homogenous
strains from these data. |
|
NIH NHLBI
1 RO1 HL67025 Chronic Ischemic MR -
Mechanisms and Novel Surgical Therapy
|
The goal of
this project is to determine the geometric valvular
mechanisms responsible for chronic ischemic mitral
regurgitation (IMR) and to define how the therapeutic
effects of ring annuloplasty and how they differ from
those of a novel trans-annular suture reparative technique
which we have shown can eliminate acute IMR. To relate
regional and global LV mechanics, future work will require
integrating the data from these two projects into
comprehensive computational models implemented with Continuity. |
|
Mark Ratcliffe, MD, (PI)
Professor of Cardiovascular Surgery,
UCSF
Julius M. Guccione, PhD, (Co-I)
Associate Professor of Cardiovascular
Surgery and Bioengineering,
UCSF |
NIH NHLBI
5 R01 HL063348-03
Quantitative Analysis of Left
Ventriculo-plasty - CHF |
This proposal builds on previous
measurement of regional stress and ventricular function
after aneurysm application in the sheep aneurysm model. It
will measure regional LV material properties before and
after aneurysm repair with a biaxial stretching apparatus.
Those ex-vivo measurements will be confirmed from magnetic
resonance measurements of regional cardiac deformation
which in conjunction with knowledge of regional cardiac
architecture and previously developed finite element
techniques will be used to calculate regional in-vivo
cardiac material properties. We rely heavily on the finite element software Continuity to analyze
the effects of changes in left ventricular geometry and
myocardial material properties on global and regional
ventricular function. |
|
Soft Tissue Biomechanics |
|
Jeffrey W. Holmes, MD, PhD (PI) and Kevin
D. Costa, PhD (co-PI)
Assistant Professors of Biomedical
Engineering, Columbia University,
New York |
NSF
BES-02-01617
Parameterization of Cardiac Wall Motion:
Reuniting Engineering and Cardiology
Teaching
BMEN-E4305
Cardiac Mechanics
|
The major goal of this project is to
develop a practical, quantitative method of evaluating
regional ventricular wall motion abnormalities from
echocardiographic images based on a non-Cartesian finite
element analysis with Continuity, which is
ideally suited due to its formulation using generalized
curvilinear coordinates, especially prolate spheroidal
coordinates. It is proposed that mapping wall motion in
terms of the radial prolate coordinate, lamda, simplifies
the parametric representation of the endocardial surface
and thus enhances the ability to detect, quantify, and
visualize wall motion abnormalities. We have two recent
publications using Continuity (Angelini et al.,
2002; Costa et al., 2001)
Course Description: This is a
graduate/advanced undergraduate course that uses Continuity as an interactive educational tool to
reinforce theoretical concepts and simulate practical
applications of topics in soft tissue biomechanics applied
to myocardium. Topics include cardiac anatomy, myocardial
constitutive properties, electrical activation,
ventricular function, ventricular-vascular coupling,
invasive and noninvasive measures of cardiac function,
models for ventricular wall stress. |
|
Cardiac Imaging - Continuity |
|
Samuel A. Wickline, MD (PI)
Professor of Medicine, Physics, and
Biomedical Engineering
Washington University School of Medicine |
NIH NHLBI
RO1 HLA-42950
Ultrasonic tissue characterization of
cardiac remodeling
RO1 HLA-63448: Microscopic cardiac
material properties in aging
|
The goals of these projects are to
evaluate the effects of aging and of angiogenesis on
cardiac remodeling after myocardial infarction. The use of
MRI tagging allows calculation of 3-dimensional strain
patterns that provide input to computational models of
ventricular function related to fundamental material
properties that determine cellular, regional, and global
cardiac systolic and diastolic function. Continuity will also be used to analyze muscular dystrophy and
diabetic cardiomyopathy that manifest both structural
(fibrosis, sarcolemmal protein defects) and functional
disturbances (abnormal energetics leading to cross-bridge
cycling abnormalities). These models will help delineate
the mechanisms responsible of the functional
abnormalities. We have also used the fiber orientation
analysis tools developed and distributed by the NBCR to
characterize remodeling in border zones of myocardial
infarction. |
| Visualization and multi-scale modeling |
|
Visual Programming Environment for
Protein Annotation |
|
Philip Bourne
University of California San Diego |
NIHMS (NIH 1 P01 GM63208)
Systematic Protein Analysis and Modeling:
(Visualization Tools for the Encyclopedia of Life) |
Three dimensional models of proteins
corresponding to a large number of sequences in the genome
of any given organism have to be annotated and sometimes
modeled. A shell script currently drives these
calculations. Replacing this script by a ViPEr-based
network will not only make this pipeline more visual but
also make it more flexible and easier to maintain. Input
nodes in such a network will correspond to organisms and
subsequent nodes will represent all computational steps
involved in the pipeline. The network will be used to
split the work into smaller chunks that will be
distributed on to the available computational resources.
The work flow propagation available in ViPEr will
take care of scheduling the next calculation once all the
input data is available from parent nodes. Once such a
network is created, computing for another organism is just
a mater of replacing the top node. |
|
Docking Tools |
|
Gabriele Varani
University of Washington |
NIH R01GM064440
RNA Recognition by the RNA
Recognition Motif (RRM) Superfamily |
Using Autodock and Autodock Toolkit
(ADT) to dock large databases against structures of
RNA and RNA-protein complexes to discover new molecules
active against infections pathogens. Improvements in
AutoDockTools to enable easier handling of RNA molecules
will facilitate this research. Grid-enabled AutoDock will
allow larger virtual screens. |
|
K.N. Houk
University of California Los Angeles |
NIH 5R01GM061402
Origins of Stereo-Selective Catalysis by
Antibodies |
Using Autodock and Autodock Toolkit
(ADT) to study antibody catalysis. This involves
quantum mechanically computed transition structures docked
into antibody binding sites to obtain insights into
stereoselctive catalysis. The goal of this research
project is to understand the mechanism by which antibody
catalysts accelerate the reaction and induce
stereoselectivity. |
|
Peter Reilly
Iowa State University
|
NSF IGERT DGE99-72653 (9/99-8/04) (PI.
D.Voytas) Computational Analysis of Hydrolase and
Carbohydrate-Binding Protein Mechanisms |
Using AutoDock and ADT to study
glucoamylase, b-amylase, a number of cellulases,
phospholipase D, and surfactant protein D by advanced
modeling methods, using available three-dimensional
structures as templates. Automated docking of
carbohydrates into the active sites of these hydrolases
and this binding protein yields optimal and suboptimal
docked protein- carbohydrate conformations, and this
allows an advanced understanding of protein
structure-function relationships. They have also developed
an advanced parameter set to estimate free energies of
carbohydrate docking to proteins. Specific studies include
binding parameters, docking into beta-amylase and
surfactant protein D (Alain Laederach) and docking into
Glycoside Hydrolase, Family 1 enzymes (beta-glucosidase
and five related hydrolases) (Tony Hill) |
|
Michael Johnson
University of Illinois at Chicago |
NIH 5R01HL057604
Development of Site Specific Antisickling |
Using Autodock and Autodock Toolkit
(ADT) for the development of new antisickling
compounds for sickle cell anemia and to design efforts for
Factor Xa inhibitors as new anticoagulants. |
| Grid services and Telescience |
|
Tomographic Reconstruction Codes |
Jose-Maria Carazo, Ph.D.
Centro Nacional de
Biotecnologia-CSIC - Campus Universidad Autonoma Madrid,
Spain 28049
|
EU and Spain / with IIEMS
EMBL BioStructure Bioinformatics & Database Projects
ART-BLOBS Parallel Electron
Tomography |
Project uses NCMIR created datasets and
NBCR developed codes to derive improved images of
three-dimensional biological structures from projections -
EM tomography. Parameters are expored to determine
appropriate parameters for application of various advanced
algorithmic approaches to tomographic reconstruction for
biomolecular structures. This group is obtaining data from
NCMIR from specimens contrasted by photo conversion and
imaged with most probable loss energy filtering to
delineate either supramolecular structures in situ, or at
much lower resolution, cell processes in their tissue
context. They then evaluate parameters that can be
adjusted to tune these and other reconstruction algorithms
to increase their utility for data of different
characteristics. They also intend to work with NBCR's
multiscale data sets and data federation approaches to
link to ones we are developing in Europe such as the
Macromolecular Structural Data Base (MSD) in Madrid and
Cambridge. |
James K. Fredrickson
Pacific Northwest National
Laboratory |
U.S. DOE 42654 10/01-10/04
Environmental Sensing,
Metabolic Response, and Regulatory Networks in the
Respiratory System |
The entire genome sequence of MR-1 has,
in essence, been determined and high throughput methods
for measuring gene expression are now available, including
mass spec-based proteome analyses developed at PNNL.
Although powerful, DNA array and proteome analyses must be
tightly coupled with other approaches to effectively
reveal the molecular details of how MR-1 functions in, and
responds to, its environment. This group is using electron
tomography in this project and parallel reconstructions
are being conducted with codes and resources NBCR
developed and maintains. |
Bridget Wilson
University of New Mexico |
ACS RPG-99-233 8/99-7/02
(Wilson), NIH GM49814 (Oliver) 8/00-7/05, NIH HL56384
10/96-10/06 (Lipscomb)
3-D reconstruction of
RBL-2H3 ER and plasma membranes |
We use the NCMIR's and NBCR's tomographic resources to: (1) determine the 3-dimensional
volume of the endoplasmic reticulum in RBL-2H3 cells and
(2) reconstruct a 3-dimensional view of a "typical"
resting and activated RBL-2H3 cell, reflecting the
dramatic changes in surface topography (and potentially
volume). We showed previously that Type 2 IP3 receptors
form large clusters within the endoplasmic reticulum
within minutes of sustained elevations in calcium induced
by receptor activation or calcium ionophore. For our
current modeling project, that attempts to predict the
effects of IP3 receptor clustering on the filling state of
the ER calcium store, we need accurate measurements of the
endoplasmic reticulum volume, shape and distribution. |
