Genomics, Proteomics and Bioinformatics: A New Era for the Biomedical Engineer Research Directions, Challenges and Applications in the Field of Genomics Raimond L. Winslow The Whitaker Biomedical Engineering Institute and Center for Computational

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Genomics, Proteomics and BioinformaticsA New
Era for the Biomedical EngineerResearch
Directions, Challenges and Applications in the
Field of GenomicsRaimond L. Winslow The
Whitaker Biomedical Engineering Institute
andCenter for Computational Medicine and
Biology,The Johns Hopkins University
Institute URL http//www.wbmei.jhu.eduCenter
URL http//www.ccmb.jhu.eduLab
URL http//www.cmbl.jhu.edu
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Vertical Integration in Biology
Confocal and 2-Photon Molecular/Cellular
Imaging Whole Cell/Patch-Clamp Recording Force
Protein Arrays Mass Spec 2-Hybrid
Interaction Assays FRET
MR Imaging Electrode Arrays Voltage
Ca2 Sensitive Dyes
Tissue Organ
Cell
Genome
Proteome
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Genomics ProteomicsData Models Statistical
Inference

• Max-Likelihood Estimation of gene-specific model
  parameters

• Regulated Genes
• Transcription/Translation
• Cell Structure/Extracellular Matrix
• Contractile Proteins
• Membrane Receptors
• Metabolism
• Ion Channels
• Ca2 Cycling Proteins
• Angiogenesis

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Genomics ProteomicsPathway Databases
Mapping Endomesoderm Gene Networks of the Sea
Urchin
http//www.its.caltech.edu/mirsky/endomeso.htm
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Genomics ProteomicsPathway Databases
http//gladstone-genome.ucsf.edu/public/PNAS_Ro1/G
protein.asp
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Genomics ProteomicsReverse Engineering of
Gene/Protein Networks

• Bayesian Networks
• Friedman et al, J. Comp. Biol. 7(3/4) 601
• Hartemink et al, Pac. Symp. Biocomp. 422

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Genomics ProteomicsDesigning Gene Networks
A
B
Gardner, TS, Cantor, CR and Collins, JJ (2000).
Construction of a genetic toggle switch in
Escherichia Coli. Nature 403 339
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Genomics ProteomicsModeling Gene/Protein
Networks

• Cell Signal Transduction
• Receptors
• Intracellular signalling pathways
• Constituents connectivity
• Spatial organization
• Molecular targets
• Metabolic Networks
• Network Dynamics
• Control
• Alliance For Cellular Signalling
  http//afcs.swmed.edu

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The CellProblem of Integration
Model
Normal
CHF
Experiment
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The CellProblem of Integration
Wier et al (1994) J. Physiol. 474(3) 463-471
Session 4.6 - Modeling of the Ionic Basis of
Arrhythmias Imperial 7, Saturday Oct 6 
400-530pm
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The CellProblem of Integration
CP
LC

• Integrate ODEs defining the model over time steps
  Dt
• Within each Dt, simulate stochastic gating of
  each statistically independent FU to model Ca2
  flux
• Appropriate abstraction of complex models may be
  highly problem specific

Local Control Model
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The CellSubsystems

• Models must be modular abstracted

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The CellCellML
CellML is an eXtensible Markup Language (XML) for
defining mathematical representations of cellular
processes http//www.cellml.org
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Tissue OrganImage-Based Models
DTMRI Fiber Angles In Cross Section
DTMRI Fiber Angles - Epicardial Surface
Epicardial Fibers FEM Model
Endocardial Fibers FEM Model
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Tissue OrganParallel Computing
Reaction-Diffusion Equation
Measure geometry H and micro-anatomical
structure Mi(x) of the heart

• canine heart at 200 mm resolution, 25106
  myocardial lattice points
• 30-50 ODEs per lattice point
• Need for parallel algorithms

Winslow et al (2000). Ann. Rev. Biomed. Eng., 2
119-155
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Tissue OrganKnowledgebases
Goals of Heart Failure Knowledgebase

• Define a database schema in which data objects
  defined at many different levels of biologicl
  organization are readily accessible to the
  database user
• Provide the user with data analysis tools that
  facilitate model development

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Cardiac Gene Expression Knowledgebase
(CaGE)http//www.cage.wbmei.jhu.edu/
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Generalized Anatomic Database Interface and
Analysis Platform