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Designing and Constructing a Set
of Fundamental Cell Models:
Application to Cardiac Disease
James B.Bassingthwaighte
University of Washington
Seattle
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Engineering and reverse engineering the route
from Genome to Function:
(Integrating Biological Systems Knowledge)
The Physiome Project
http://www.physiome.org
Tissue
Cell
Molecule
Genes
Organism
Health
Organ
Structure and Function:
• Biomedical Problem Formulation
• Quantitative Approaches
• Engineering Methods
• Mechanistic System Modeling
• Databasing & Dissemination
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The Physiome and the Physiome Project
• The “Physiome”, like the Genome, is a 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 and vice versa.
• 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
function, logical prediction, and integrative
quantitative modeling for critical projections.
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Physiome and Physiome Project
• The models of genomic, metabolic, or integrative systems
should, via iteration with carefully designed experiments,
resolve contradictions amongst prior observations and
interpretations.
• Reasonably comprehensive and accurate models will
demonstrate emergent properties. This is the “reverse
engineering” of biology. Some of these will be applied to
clinical diagnosis and the evaluation of care.
• Databases, concepts, descriptions, and models are to be put in
the public domain, an open system.
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Structure with Function
• The Genome, and the Transcriptome.
THE PHYSIOME:
• The physico-chemical status.
• Descriptions of the Proteome, of solutes, bilayers,
organelles, organs, organisms.
• Quantitative measures of structural components,
e.g. protein and solute levels in cells and organelles,
volumes, surface areas, material properties, etc.
(The Morphome)
• Schema of interactions between the components.
Regulatory apparatus for gene expression and
metabolism. (The Metabolome)
• Computational models (genes +milieu organism).
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Three Incentives for Developing
the Physiome
• To develop understanding of a mechanism
or a phenomenom: basic science.
• To determine the most effective targets for
therapy, either pharmaceutic or genomic.
• To design artificial or tissue-engineered,
biocompatible implants.
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An example: LBBB
Left Bundle Branch Block of the Cardiac
Conduction System
Auscultation: Reverse splitting of the second heart sound
ECG: Wide QRS complex and often late T wave
X-ray: Moderate cardiac enlargement
Thallium scan: Low flow in the septum
PET scan: Decreased septal glucose uptake,
but normal septal fatty acid uptake.
The imaging gave three clues to the physiology.
How can the observations be explained?
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Electrical activation of the normal heart
sinus node
left atrium
His bundle
AV node
bundle branches
right ventricle
Purkinje fibers
Prinzen et al., 2000
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Schematics of electrical activation
RV apex pacing
left bundle branch block
X
Prinzen et al., 2000
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Explaining what is observed in
Left Bundle Branch Block
ECG: Wide QRS complex and often late T wave
The RBB is activated normally, and excitation proceeds
normally over the RV, but since the left branch of the bundle of
His is blocked the spread of
activation into the left ventricular
muscle is delayed 50 to 100 ms,
broadening the QRS complex,
and delaying the repolarization
phase (late T wave)
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MRI tagging of Cardiac Contraction
Pacing
spike
ECG
...
Presat.
pulse
50ms
90ms
130ms
...
Gx
RF
Tagging pulse
Delay = 50 ms
Delay = 90 ms Delay = 130 ms
(Prinzen, Hunter, Zerhouni,1999)
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Explaining what is observed in
Left Bundle Branch Block
Auscultation: Reversed splitting of S2 (second
heart sound)
The RBB is activated normally, but activation of the left
ventricle is delayed 50 to 100 ms, so that aortic valve closing
is delayed and is later than pulmonic closing, rather than
earlier. During inspiration increased RV filling, delaying
pulmonic valve closure, shortens (rather than lengthening)
the interval between pulmonic and aortic valve closure:
reversed respiratory influence on second sound splitting
interval.
Normally, Insp  longer A2–P2 , but here Insp  shorter P2–A2
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 Segment length
Effect of RV apex pacing on regional
LV epicardial fiber strain
early-activated
late-activated
Prinzen et al,
Am. J. Physiol, 1990
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Distribution of external work in the LV wall
Atrial pacing
RV apex pacing
LV free wall pacing
.
(mJ/g) 8
.
.
septum
anterior
*
*
posterior
00
Fiber length
Fiber stress
Fiber stress
Fiber stress
Prinzen et al, J Am Coll Cardiol, 1999
Fiber length
Fiber length
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To explain what is seen in LBBB:
Thallium scans: Decreased septal blood flow relative
to rest of LV because local demand is reduced.
Decreased septal mass due to local atrophy.
PET Glucose Uptake: Decreased septal uptake due to
shift away from glucose with diminished demand
relative to supply. PET data show normal FA uptake.
Regional FA uptake is matched to local flow.
X-ray: LV hypertrophy: Hypertrophic free wall due to
increased workload and low contractile efficiency. This
is partially attributable to increased wall tension with
LV cavity volume increase:
T=PxR.
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Cardiac fiber
structuring:
LV base
From Torrent-Guasp, 1998
LV near
the apex
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Rabbit Heart: Epicardial fibers – blue
Subendocardial fibers - yellow
From Vetter and McCulloch, UCSD
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Integration by Computation: The Cardiome
• Transport:
• UW: Flows, uptake (O2, fats)
• Cardiac Mechanics:
• Auckland Univ: P.Hunter
• UCSD: McCulloch
• Maastricht: Arts, Prinzen,
Reneman
• JHU: W.Hunter
• Action Potentials:
• Oxford U: D. Noble
• Johns Hopkins: Winslow
• Case-Western: Rudy
• Cardiac excitatory spread:
•
•
•
•
CWRU: Rudy et al.
Johns Hopkins: Winslow
Syracuse: Jalife
UCSD: McCulloch
N.Smith, P. Hunter,et al. 1998
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What are the mechanisms for the
responses in
Left Bundle Branch Block?
Thallium scans: How is local flow regulated?
PET Glucose Uptake: How is glycolysis
regulated?
MR Strain Patterns: How do structure,
excitation, and contraction combine to produce
these?
X-ray LV hypertrophy: What regulates actin
and myosin expression?
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Excitation-Contraction Coupling
• Cooperativity
• Mechanical Feedback
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The
Motor
Units
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Energy Use depends on shortening velocity:
g +g V
0
1
ATP
ATP
ADP
WEAK


f
STRONG
Weak-Strong vs. Attached-Detached
Mechanical Feedback
Landesberg/Sideman, 1998
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The Conservative Phys-chem cell
(no protein synthesis or proteolyis)
• Balances mass, charge, volume, energy, reducing
equivalents, concentrations
• Serves as a primitive for expanded models
•
•
•
•
•
RBC, prokaryote, eukaryote, myocyte, B-cell
Serve as entry to databases
Component of healthy and diseased tissues
Basis for multicellular integrated systems models
Understanding via metabolic control analysis of networks
• Test bed for mechanistic pharmacodynamic
models and selection for drug design and for
genomic intervention
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The glycolytic conservative cell
(with eternal proteins)
e.g. arep.med.harvard.edu,
Edwards, Palsson,Church et al.
Ca2+
Substrates
3Na+
ATP
Metabolites
Ca2+
Ca2+
K+
Glycolysis
RBC
pH balance
~P balance
Purine balance
Osmotic balance
Water balance
Charge
H+
neutrality
Na+
Redox
state
calmodulin
Free Energy
Na+
3Na+
ATP
H+
2 K+
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The conservative cell with eternal proteins
Substrates INaCa
Ip(Ca)
ATP
Na+ Ca2+
Glycolysis,
fatty acid
TCA
OxPhosph
Endoplasmic
reticulum
pH
~P balance
Purine balance
Osmotic balance
Water balance
ATP
Na+
Na+
Ca2+
K+
Charge
H+
neutrality
Redox
state
calmodulin
Free Energy
Na+
ATP
H+
K+
INaK
INa
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The sustainable metabolic muscle cell
ICa,b
ICa,K
Substrates INaCa
Ip(Ca)
OxPhosph
TCA
ATP
Ca2+
Na+ Ca2+
K+
Ca2+
T-tubule ICa
subspace
K
+
K
Ca2+
+
RyR
calseq
Ca2+
Sarcoplasmic
reticulum
ATP regulation
pH, P & K
+
Charge
K
neutrality +
calmodulin
Leak
Ca2+
K
TRPN
+
Na+
Ca2+
IKs
IK1
IKp
calmodulin
Ca2+
ATP
IKr
Na+
Na+
Na+
INa
INa,b
Ito1
ATP
H+
K
+
INaK
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The cardiac muscle cell
ICa,b
ICa,K Substrates INaCa
Ip(Ca)
ATP
Ca2+
T-tubule ICa
subspace
Na+ Ca2+
K+
Ca2+
K
Glycolysis
+
RyR
calseq
K
OxPhosph
TCA
Ca2+
+
K
calmodulin
Ca2+
IK1
+
IKp
K
Leak
Sarcoplasmic
reticulum
+
ATP
Na+
Ca2+
Na+
Na+
Na+
INa
INa,b
IKs
+
K
Ca2+
IKr
Ito1
ATP
(building from Luo-Rudy 1994-2001
and Winslow et al. 1999)
H+
K
+
INaK
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Conclusions:
• Conservative cell models provide a basis for a host
of specific applications.
• Their behavior is innately complex and highly
dependent on the conditions.
• Computability is a major issue if models are to be
used are practical aids to thinking.
• Even now they provide short-term prediction of
the consequences of intervention.
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END
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