Die Dozenten der Informatik-Institute der Technischen Universität
Braunschweig laden im Rahmen des Informatik-Kolloquiums zu folgendem
Vortrag ein:
Srboljub M. Mijailovich, Ph.D., Harvard School of Public Health:
Quantitative Bioengineering Analysis of Muscle Mechanics and Metabolism
Beginn: 23.10.2009, 10:00 Uhr
Ort: TU Braunschweig, Gauß-IT-Zentrum, Hans-Sommer-Str. 65,
Seminarraum 012
Webseite:
http://www.ibr.cs.tu-bs.de/cal/kolloq/2009-10-23-mijailovich.html
Kontakt: Prof. Hermann G. Matthies, PhD
Using the methods of engineering analysis, we have developed a
computational platform that incorporates current knowledge of molecular
structure, biochemical energetics, and actomyosin binding kinetics to
describe muscle contraction. Developed comprehensive model can be used to
(1) generate new mechanistic hypotheses concerning the functions of the
contractile proteins myosin and actin and (2) quantitatively evaluate
the roles of accessory and regulatory proteins in contraction.
This computational model is a powerful analytical and predictive tool
in studies of muscle physiology in health and disease. Presently,
no models of contraction account for complications due to both (1)
extensibility of the actin and myosin filaments and (2) Ca2+ regulation of
contraction. Filament extensibility results in non-uniform load transfer
along the thick and thin filaments, which introduces variability in
the stress and strain of the myosin heads during their interactions
with actin. These effects must be taken into account to understand
how cross-bridge forces affect chemical transitions in the actomyosin
ATPase cycle and vice versa. Further, quantitative understanding of Ca2+
regulation will allow (1) more accurate predictions of the macroscopic
mechanical and energetic consequences of specific regulatory events
and (2) more accurate explanations of macroscopic events in terms of
underlying molecular processes.
These problems are addressed via a multidisciplinary approach that
spans engineering science, computational science, and biophysics and
rests entirely upon first principles. The developed model integrates
a critical missing element – filament extensibility – with recent
advances in understanding the (1) biochemical states of myosin; (2)
transitional rate constants in the actomyosin ATP hydrolysis cycle;
(3) function of myosin molecular motors in the thick and thin filament
lattice (sarcomere); and (4) Ca2+ regulation of myosin binding. The model
combines either probabilistic or stochastic actomyosin binding kinetics
with finite element analysis including spatially discrete sarcomere
lattice consistent with the periodicities of the thick and thin filaments.
The developed computational model invokes unifying principles that
apply to the actomyosin cycle regardless of muscle type and it has
sufficient flexibility to account for contraction kinetics and regulation
of contraction in different muscle types. Quantitative modeling of
contraction is ultimately essential for understanding the molecular basis
for a wide range of syndromes and diseases, such as airway narrowing in
asthma and weakness of both heart and skeletal muscles in heart failure.
Die Dozenten der Informatik-Institute der Technischen Universität
Braunschweig laden im Rahmen des Informatik-Kolloquiums zu folgendem
Vortrag ein:
Srboljub M. Mijailovich, Ph.D., Harvard School of Public Health:
Molecular Origins of Airway Narrowing: Multiscle Model Predictions of
Hyperresponsiveness in Asthmatics
Beginn: 22.10.2009, 10:00 Uhr
Ort: TU Braunschweig, Gauß-IT-Zentrum, Hans-Sommer-Str. 65,
Seminarraum 012
Webseite:
http://www.ibr.cs.tu-bs.de/cal/kolloq/2009-10-22-mijailovich.html
Kontakt: Prof. Hermann G. Matthies, PhD
We have developed a theoretical multiscale model to quantify how
alterations in the cross-bridge kinetics of airway smooth muscle (ASM)
and in the airway wall remodeling affect the symptoms of asthma and
chronic obstructive pulmonary disease (COPD). By taking into account
the coupling between ASM contraction and the dynamics of breathing,
the new model is able to predict the hyperreactivity of the asthmatic
airways and their hypersensitivity to increasing doses of contractile
agents. The latter could not be reproduced by previous models that
considered static equilibrium between the isometric ASM force and the
mean transpulmonary pressure.
In the presented model the airway caliber – proportional to the ASM
length – is dynamically determined from the instantaneous balance
between airway wall reaction force (AWRF) and the ASM contractile
force. The AWRF is derived from transmural pressure across the airway
wall and the forces of parenchymal tethering: it is computed from the
elasticity and geometry of the airway wall, the tethering of the airway to
the lung parenchyma, and the state of lung inflation. The resulting force
is equivalent to an instantaneous load acting on the ASM in situ. This
force depends on the transpulmonary pressure variation and the pressure
drop along the airway tree during breathing. The ASM contractile force
and length are determined using Mijailovich’s molecular model of smooth
muscle contraction and regulation, based on the perturbed equilibria of
myosin binding. The instantaneous airway luminal area and resistance are
obtained from the ASM length for each airway generation in Weibel’s
bronchial tree. The pressure drop along the tree is computed from the
resistance and the instantaneous flow rate. The calculations include the
effect of deep inspirations (DI) superimposed over quiet tidal breathing
for normal, COPD, and asthmatic airways.
Our results show that at low doses of histamine, ASM reaches dynamical
equilibrium at long lengths, and the airways are completely open and
compliant. However, at histamine doses above a “critical” value, the
ASM drastically shortens, and the airways are severely constricted and
stiff. In COPD and asthmatic airways the critical dose is significantly
lower than in normal airways; above this dose the degree of ASM
shortening, and therefore airway constriction, are both significantly
greater than in normal airways. In this case, DI may not be sufficient to
open the asthmatic airways. The agreement between the model predictions
and clinical observations suggests that both the hyperreactivity and
hypersensitivity observed in asthmatic and COPD airways can be explained
by a single mechanism – perturbed equilibria of myosin binding.
Die Dozenten der Informatik-Institute der Technischen Universität
Braunschweig laden im Rahmen des Informatik-Kolloquiums zu folgendem
Vortrag ein:
Srboljub M. Mijailovich, Ph.D., Harvard School of Public Health:
Molecular Origins of Airway Narrowing: Multiscle Model Predictions of
Hyperresponsiveness in Asthmatics
Beginn: 22.10.2009, 10:00 Uhr
Ort: TU Braunschweig, Gauß-IT-Zentrum, Hans-Sommer-Str. 65,
Seminarraum 012
Webseite:
http://www.ibr.cs.tu-bs.de/cal/kolloq/2009-10-22-mijailovich.html
Kontakt: Prof. Hermann G. Matthies, PhD
We have developed a theoretical multiscale model to quantify how
alterations in the cross-bridge kinetics of airway smooth muscle (ASM)
and in the airway wall remodeling affect the symptoms of asthma and
chronic obstructive pulmonary disease (COPD). By taking into account
the coupling between ASM contraction and the dynamics of breathing,
the new model is able to predict the hyperreactivity of the asthmatic
airways and their hypersensitivity to increasing doses of contractile
agents. The latter could not be reproduced by previous models that
considered static equilibrium between the isometric ASM force and the
mean transpulmonary pressure.
In the presented model the airway caliber – proportional to the ASM
length – is dynamically determined from the instantaneous balance
between airway wall reaction force (AWRF) and the ASM contractile
force. The AWRF is derived from transmural pressure across the airway
wall and the forces of parenchymal tethering: it is computed from the
elasticity and geometry of the airway wall, the tethering of the airway to
the lung parenchyma, and the state of lung inflation. The resulting force
is equivalent to an instantaneous load acting on the ASM in situ. This
force depends on the transpulmonary pressure variation and the pressure
drop along the airway tree during breathing. The ASM contractile force
and length are determined using Mijailovich’s molecular model of smooth
muscle contraction and regulation, based on the perturbed equilibria of
myosin binding. The instantaneous airway luminal area and resistance are
obtained from the ASM length for each airway generation in Weibel’s
bronchial tree. The pressure drop along the tree is computed from the
resistance and the instantaneous flow rate. The calculations include the
effect of deep inspirations (DI) superimposed over quiet tidal breathing
for normal, COPD, and asthmatic airways.
Our results show that at low doses of histamine, ASM reaches dynamical
equilibrium at long lengths, and the airways are completely open and
compliant. However, at histamine doses above a “critical” value, the
ASM drastically shortens, and the airways are severely constricted and
stiff. In COPD and asthmatic airways the critical dose is significantly
lower than in normal airways; above this dose the degree of ASM
shortening, and therefore airway constriction, are both significantly
greater than in normal airways. In this case, DI may not be sufficient to
open the asthmatic airways. The agreement between the model predictions
and clinical observations suggests that both the hyperreactivity and
hypersensitivity observed in asthmatic and COPD airways can be explained
by a single mechanism – perturbed equilibria of myosin binding.
Die Dozenten der Informatik-Institute der Technischen Universität
Braunschweig laden im Rahmen des Informatik-Kolloquiums zu folgendem
Vortrag ein:
Srboljub M. Mijailovich, Ph.D., Harvard School of Public Health:
Quantitative Bioengineering Analysis of Muscle Mechanics and Metabolism
Beginn: 23.10.2009, 10:00 Uhr
Ort: TU Braunschweig, Gauß-IT-Zentrum, Hans-Sommer-Str. 65,
Seminarraum 012
Webseite:
http://www.ibr.cs.tu-bs.de/cal/kolloq/2009-10-23-mijailovich.html
Kontakt: Prof. Hermann G. Matthies, PhD
Using the methods of engineering analysis, we have developed a
computational platform that incorporates current knowledge of molecular
structure, biochemical energetics, and actomyosin binding kinetics to
describe muscle contraction. Developed comprehensive model can be used to
(1) generate new mechanistic hypotheses concerning the functions of the
contractile proteins myosin and actin and (2) quantitatively evaluate
the roles of accessory and regulatory proteins in contraction.
This computational model is a powerful analytical and predictive tool
in studies of muscle physiology in health and disease. Presently,
no models of contraction account for complications due to both (1)
extensibility of the actin and myosin filaments and (2) Ca2+ regulation of
contraction. Filament extensibility results in non-uniform load transfer
along the thick and thin filaments, which introduces variability in
the stress and strain of the myosin heads during their interactions
with actin. These effects must be taken into account to understand
how cross-bridge forces affect chemical transitions in the actomyosin
ATPase cycle and vice versa. Further, quantitative understanding of Ca2+
regulation will allow (1) more accurate predictions of the macroscopic
mechanical and energetic consequences of specific regulatory events
and (2) more accurate explanations of macroscopic events in terms of
underlying molecular processes.
These problems are addressed via a multidisciplinary approach that
spans engineering science, computational science, and biophysics and
rests entirely upon first principles. The developed model integrates
a critical missing element – filament extensibility – with recent
advances in understanding the (1) biochemical states of myosin; (2)
transitional rate constants in the actomyosin ATP hydrolysis cycle;
(3) function of myosin molecular motors in the thick and thin filament
lattice (sarcomere); and (4) Ca2+ regulation of myosin binding. The model
combines either probabilistic or stochastic actomyosin binding kinetics
with finite element analysis including spatially discrete sarcomere
lattice consistent with the periodicities of the thick and thin filaments.
The developed computational model invokes unifying principles that
apply to the actomyosin cycle regardless of muscle type and it has
sufficient flexibility to account for contraction kinetics and regulation
of contraction in different muscle types. Quantitative modeling of
contraction is ultimately essential for understanding the molecular basis
for a wide range of syndromes and diseases, such as airway narrowing in
asthma and weakness of both heart and skeletal muscles in heart failure.
