Аннотация
There has been significant progress towards the development of highly
integrative computational models of the cardiac myocyte over the
past decade. Models now incorporate descriptions of voltage-gated
ionic currents and membrane transporters, mechanisms of calcium-induced
calcium release and intracellular calcium cycling, mitochondrial
ATP production and its coupling to energy-requiring membrane transport
processes and mechanisms of force generation. There is an extensive
literature documenting both the reconstructive and predictive abilities
of these models and there is no question that an interplay between
quantitative modelling and experimental investigation has become
a central component of modern cardiovascular research. As data regarding
the cardiovascular proteome in both health and disease emerge, integrative
models of the myocyte are becoming useful tools for interpreting
the functional significance of changes in protein expression and
post-translational modifications (PTMs). Data of particular importance
include information on: (a) changes of expressed protein level, (b)
changes of protein PTMs, (c) protein localization, and (d) protein-protein
interactions, as it is often possible to incorporate and interpret
the functional significance of such findings using computational
models. We provide two examples of how models may be used in this
fashion. In the first example, we show how information on altered
expression of the sarcoplasmic reticulum Ca$^2+$-ATPase, when
interpreted through the use of a computational model, has provided
key insights into fundamental mechanisms regulating cardiac action
potential duration. In the second example, we show how information
on the effects of phosphorylation of L-type Ca$^2+$ channels,
when interpreted through the use of a model, provides insights on
how this post-translational modification alters the properties of
excitation-contraction coupling and risk for arrhythmia.
- 15611013
- animals,
- biological,
- cells,
- computer
- expression
- extramural,
- gene
- gov't,
- humans,
- interaction
- mapping,
- models,
- muscle
- myocardium,
- n.i.h.,
- non-u.s.
- p.h.s.,
- post-translational,
- processing,
- profiling,
- protein
- proteome,
- proteomics,
- regulation,
- research
- simulation,
- support,
- u.s.
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