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The Physiome: Genes to Organism. Modeling toward Human Health. ( Model Reproducibility, Databasing, and Covenient Dissemination). James Bassingthwaighte, James H. Caldwell, 1 Bioengineering, 1,2 Radiology, 2 Medicine University of Washington, Seattle. Supported by ORNL NIH Program Office.

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The Physiome: Genes to Organism.Modeling toward Human Health.( Model Reproducibility, Databasing, and Covenient Dissemination)

James Bassingthwaighte, James H. Caldwell,

1Bioengineering, 1,2Radiology, 2Medicine

University of Washington, Seattle

Supported by ORNL NIH Program Office


From genome to function integrating knowledge of biological systems l.jpg

From Genome to Function:(Integrating Knowledge of Biological Systems)

Health

Organism

The Physiome Project

Organ

Tissue

  • Gene, Structure & Function:

  • Experiments, Databases

  • System description

  • Quantitative system modeling

  • Archiving & dissemination

Cell

Molecule

Genes


The physiome and the physiome project l.jpg

The Physiome and the Physiome Project

  • The “Physiome” is the quantitative description of the functional behavior of the physiological state of an individual of a species. In its fullest form it should define relationships from organism to genome.

  • The “Physiome Project” is a concerted effort to define the Physiome through databasing and through the development of a sequence of model types: schema of interactions, descriptions of structure and functional relationships, and integrative quantitative modeling for logical prediction and critical projections.


Physiome and physiome projects l.jpg

Physiome and Physiome Projects

  • Integrative models of genomic, metabolic, and intact in vivo systems should, via iteration with carefully designed experiments, resolve contradictions among prior observations and interpretations.

  • Comprehensive, accurate and realistic models will demonstrate emergent properties not inherent to the individual components, but apparent in the intact organism.

  • The “reverse engineering” of biology will aid clinical diagnosis and the design and the evaluation of therapy.

  • Gene regulatory networks, though difficult to construct, and almost impossible to validate, have their effects through higher level networks of cellular metabolism, tissue and organ function. These well identified systems serve as boundary conditions for proposed genetic networks, and serve also as the basis on which to explore the governance of transcription.

  • Databases, concepts, descriptions, and models should be in the public domain, in an open system fostering rapid progress in science.


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Modeling Approach: Use modular construction and use module reduction to gain speed (compromising robustness)


The cardiome multiscale modeling is required to cover the range of levels of function l.jpg

Health

Organism

Structure of heart defines

spread of excitation

(Mcculloch, UCSD)

Organ

Tissue

Cell

Molecule

The Human Physiome

Gene

Ion channel activation

requires metabolism:

Muscle contraction follows

ion channel activation:

Beard, Jafri, Kemp et al

The Cardiome: multiscale modeling is required to cover the range of levels of function

Contracting heart driven by

spread of excitation (Hunter & Smith in Auckland, with D.Beard’s coronaries)


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Modeling and Hypothesis testing

  • Formulating an hypothesis integrates the ideas.

  • Testing and disproving hypotheses is a secure route to the advancement of scientific knowledge. Use Platt’s approach1.

  • The testing requires analysis of real data, and for complex hypotheses, the simultaneous accounting for multiple and diverse data sets.

  • Because biological systems are so deeply interconnected, meaningful cause-and-effect modeling necessitates a multiscale modular approach.

  • Here we tackle the application of modeling analysis to the estimation of regional myocardial blood flow, seeking diagnostic information via comparisons of maps of flows at rest and during vasodilatory stress.

1. Platt JR. Strong inference. Science 146: 347-353, 1964.


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The hypothesis to be tested:

  • Quantitative modeling analysis improves the diagnostic accuracy of regional myocardial blood flows and of regional flow reserve in patients with regional ischemic episodes with or without compromised cardiac ejection.

  • Background:

    • In the normal heart there is an 8 to 10-fold range of regional blood flows at any particular instant. The relative local flows are quite stable over time. This means that a low flow region is not necessarily ischemic.

    • Flows must be estimated indirectly, as flow per gram of tissue, and non-invasively, using PET, MRI, SPECT, or other technique.

    • Analysis of transients in marker concentrations is common to all of these technical approaches.


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Myocardial Flow Heterogeneity in Awake Baboons

The distribution of

regional flows, in voxels

of about 0.5% of LV

mass, shows a relative

dispersion (SD/mean)

of 25 to 30% in the LV,

and more in the heart as

a whole. RV flows are

70% of LV flows.

(Data from 13 awake

baboons at rest.)

(King, Bassingthwaighte, Hales, and Rowell. Circ Res.57: 285-295, 1985. Fig 4)


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Myocardial capillaries within sheets of cardiac muscle

Capillaries parallel muscle fibers within myocardial sheets (one capillary per cell)

from Bassingthwaighte, Yipintsoi and Harvey, Microvasc. Res. 1964


Regional fatty acid uptake and flow are in constant proportion l.jpg

PS

Flow

Regional Fatty Acid Uptake and Flow are in Constant Proportion

To fit these data, there

must be increased density

of fatty acid transporters

in higher flow regions.

This implies that transporter

transcription is higher

in higher flow regions.

J. Caldwell et al.

Am J. Cardiol. 1994


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Regional Cardiac Oxygen Metabolism using 15O-oxygen and PET

Results show that MRO2 versus flow parallels palmitate uptake versus flow


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Estimating Regional Oxygen Consumption in vivo

  • Single breath inhalation of 15O-oxygen using PET

  • Image reconstruction at 2-second intervals provides time course of 15O in many regions of interest (ROI)

  • 15O -oxygen is reduced to form 15O -water

  • The fraction of the tracer oxygen transformed, times the total oxygen entering the tissue per unit time = oxygen consumption rate

Li Z, Yipintsoi T, and Bassingthwaighte JB. Nonlinear model for capillary-tissue oxygen transport

and metabolism. Ann Biomed Eng 25: 604-619, 1997.


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100 m

Capillaries are parallel (5 mm diam., 800 mm long) and radial intercapillary distances for diffusion are < 20 microns.

The Supply Side

(Bassingthwaighte, Yipintsoi & Harvey, 1974)


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Hexagonal arrangement of capillaries and muscle fibers allows simplified computation


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General blood-tissue exchange model


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Dual Oxygen/Water Modelfor analyzing PET images by Residue detection

H2O

H2O


The process of transport and exchange of oxygen l.jpg

+ Mb MbO

The Process of Transport and Exchange of Oxygen


Schematic diagram of the model capillary tissue exchange unit l.jpg

4-region Krogh cylinder axially-distributed model

convection

diffusion

permeation

reaction

consumption

production

facilitated transport

4 regions * 4 species = 16 nonlinear PDEs

Schematic Diagram of the Model:Capillary-Tissue Exchange Unit


Equations for o 2 and co 2 saturations of hemoglobin s hbo2 and s hbco2 l.jpg

invertible Hill-type equations:

[O2] and [CO2] can be obtained from SHbO2 and SHbCO2analytically…

Equations for O2 and CO2 Saturations of Hemoglobin: SHbO2 and SHbCO2

Plasma CHbO2 and CHbCO2 can be expressed in terms of PO2 and PCO2 by Henry’s law: [O2]=O2PO2, [CO2]= CO2PCO2.

Modified Hill coefficients KHbO2 and KHbCO2 account for the influences of pH and nonlinear O2-CO2interactions.

KHbO2 and KHbCO2 also depend on an equilibrium constant K4’ for O2 binding Hb which varies with PO2, PCO2, pH, [DPG], T.


Equations for modified hill coefficients k hbo2 and k hbco2 l.jpg

K4”, n0, n1, n2, n3, n4 are estimated so as to get proper forms and shifts in HbO2 & HbCO2dissociation curves w.r.t. PO2, PCO2, pH, [DPG], T.

Subscript “S” refers to the standard physiological levels in RBCs

Equations for Modified Hill Coefficients: KHbO2 and KHbCO2

( Dash and Bassingthwaighte, Ann. Biomed. Eng 2004 )


Nonstandard oxyhemoglobin hbo 2 dissociation curves l.jpg

Bohr effect

pH 

PCO2

[DPG] 

T 

Nonstandard Oxyhemoglobin (HbO2) Dissociation Curves


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Exchange Systems

Pathways of Oxygen and Carbon Dioxide Transport and Exchange – A Big Picture


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Clinical Need

  • PET Myocardial Perfusion Studies

    • Offer diagnostic improvement in all patient categories

    • Can provide quantification, gives absolute rather than relative flow

      • Important in diabetes, microvessel disease and assessing significance of coronary stenosis

    • No commercially available software for flow quantification

  • Cardiac PET estimated to grow

    • In US, # of studies grew 45%/yr over last 10 yrs, anticipate 10%/yr 

    • In China: 6 sites 2007. Anticipate minimum of 30 sites in 2010

    • No PET in Beijing in 2000. In 2005, 3,400 procedures*

      • 2005, one site doing cardiac PET

        • ~100 studies but 10% more studies than oncology in the 40 to 60 age group

 courtesy of Bracco®

* Nuc Med Comm., 28:661, 2007


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Quantitative PET Myocardial Perfusion Imaging: Integrated Image Manipulation, Modeling and Display for the Clinician

Overall Goal: Provide a user-friendly analysis tool to the PET community for estimating regional myocardial blood flow quantitatively, using PET imaging of [13N]-ammonia and [82Rb]-rubidium

Team: James B. Bassingthwaighte, MD, PhD, James H. Caldwell, MD

Adam M. Alessio, PhD, Erik Butterworth, Support: Coulter Foundation


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Rationale for Quantitative Myocardial Perfusion Imaging

  • Non-invasive measure of absolute coronary flow reserve

    • Anatomic stenosis does not equal physiology and is not prognostic

  • Balanced ischemia

    • 3 vessel disease w/out a normal region

  • Abnormal Coronary Flow Reserve:

    • Occurs in aging, hypertrophy, post- transplant vasculopathies, endothelial dysfunction.

    • The problem is that when regional differences are reduced a qualitative scan does not distinguish ischemic from normal regions, or distinguish one of low reserve from one with adequate reserve since the data are on the flat part of the curves (right).

Stress flow

coronary flow reserve

Rest flow

Gould, Am J Cardiol, 1974


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Goal 2: Quantification of Myocardial Blood Flow

NH3 Blood-Tissue Exchange Model

Capillary

Vp

Dp

13NH4

Flow

PSMig

13NOUT

PSg

13NIN

Disf

Visf

PSMipc

PSpc

Myocyte

G

13N-glutamine (Mi)

13NH4

13N-glutamate (Ma)

Vpc

Dpc

13N-urea


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Quantification of Myocardial Blood Flow

MBF Methods: 13N-NH3 injection into antecubital vein, obtain concentration time curves from LA(input function) and from myocardium (Residue functions).

Same ROI during Stress

ROI at Rest


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Goal 2: Quantification of Myocardial Blood Flow

Coronary Short-axis Equivalent

Circumflex

Stress Polar MBF

All Slices

Stress PET

Mid-ventricle slice

> 95%

> 70%

LAD

Bull’s eye plot:

Apex at center,

Septum at left.

Anterior down.


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Physician’s Summary

The qualitative maps, left column,

suggest modest flow compromise

in posterior wall near base but not

elsewhere.

The quantitative maps, center

column, show low flow

everywhere at rest, but severe

compromise in flows everywhere

but especially in the LV free wall

and posteriorly. The flow reserve

map shows only one region (#9,

white) with near normal reserve.

Diagnosis: nearly global ischemia.


15 o oxygen studies show that l.jpg

15O-oxygen studies show that:

  • Regional flows and oxygen consumption are

    • Almost proportional (linear with positive intercept)

    • Demonstrate near neighbor positive correlation

    • Follow fractal statistical relationship

  • Results extend the observations of Caldwell et al (Am J Physiol 1994) that fatty acid uptake and flow are linearly related.

  • Reinforces concept that flow is determined by tissue’s metabolic needs.


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Conclusions re the distribution of energy utilization

  • Parts of the heart use more flow, fat, sugar, and oxygen (and presumably ATP) than other parts. Regionally there is up- or down-regulation of transporters and enzymes.

  • Cardiac geometry is variegated, local conduction velocities vary widely, fibre bundles slide across one another, sarcomere shortening is regionally varied.

  • Some parts work harder than others. ATP use by myosin ATPase, i.e. the cross-bridge and force generation, dominates the variation in local demand for substrates for energy production.

  • This result infers that the normal heterogeneity of regional flows is based on local mechanical functional differences?


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Thanks

Colleagues and

Collaborators at UW

Postdoctoral Fellows

and Students at UW

Visiting Professors

Keith Kroll*

Dan Beard

Jim Caldwell

Eric Feigl

Martin Kushmerick

Ken Krohn

Jeanne Link

Zheng Li

Tom Lewellen

Maxwell Neal

* deceased

Lisa Schwartz

Lori Gustafson

Jim Revenaugh

Dwight Stapleton

Michael Kellen

Kalyan Vinnakota

Coert Zuurbier

Jans Rijken

Brian Carlson

Tada Yipintsoi

Andreas Deussen

Santibrata Ghosh

Andras Eke

Ulrich Decking

Ger van der Vusse

Rob Reneman

Frits Prinzen


Appreciation l.jpg

Appreciation


3 d heart model a single slice finite element modeling of lbbb l.jpg

Strain

LV

Free

Wall

0

Septum

3-D heart model, a single slice:Finite Element modeling of LBBB

3 mm slice thickness at mid-LV

(from Alex Veress, U. Washington)


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Conclusions

  • Realistic clinically useful models are often complicated, even complex.

  • Spatially distributed models are commonly required, but these are not more complicated than compartmental models, just more realistic.

  • Models are in day-to-day use in medical practice using imaging.

  • First principle models provide insight into the biology and can be built upon

  • Model archiving is essential


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Conclusions re the distribution of regional flows in the normal heart

  • Regional flows correlate with substrate and oxygen consumption (and presumably ATP). There is regional up- or down-regulation of transporters (fatty acid).

  • Normal cardiac geometry is variegated, conduction velocities vary, fibre bundle directions vary from endo- to epicardium, sarcomere shortening is regionally varied.

  • Some parts work harder than others. ATP use by myosin ATPase, i.e. the cross-bridge and force generation, dominates the local demand for substrates for energy production.

  • This can account for the heterogeneity in flow distribution when there is a vasodilatory response to increased local work and a diminution in vasodilatory influence when regional work decreases.

  • Myocardial flow heterogeneity, normal, is a result of uneven workloads and metabolism, presumable due to a combination of the geometric arrangements and of the timing of activation.


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