[Show abstract][Hide abstract] ABSTRACT: Recently, a number of ion channel mutations have been identified in the smooth muscle cells of the human jejunum. Although these are potentially significant in understanding diseases that are currently of unknown etiology, no suitable computational cell model exists to evaluate the effects of such mutations. Here, therefore, a biophysically based single cell model of human jejunal smooth muscle electrophysiology is presented. The resulting cellular description is able to reproduce experimentally recorded slow wave activity and produces realistic responses to a number of perturbations, providing a solid platform on which the causes of intestinal myopathies can be investigated.
PLoS ONE 08/2012; 7(8):e42385. DOI:10.1371/journal.pone.0042385 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Na(v)1.5 sodium channels, encoded by SCN5A, have been identified in human gastrointestinal interstitial cells of Cajal (ICC) and smooth muscle cells (SMC). A recent study found a novel, rare missense R76C mutation of the sodium channel interacting protein telethonin in a patient with primary intestinal pseudo-obstruction. The presence of a mutation in a patient with a motility disorder, however, does not automatically imply a cause-effect relationship between the two. Patch clamp experiments on HEK-293 cells previously established that the R76C mutation altered Na(v)1.5 channel function. Here the process through which these data were quantified to create stationary Markov state models of wild-type and R76C channel function is described. The resulting channel descriptions were included in whole cell ICC and SMC computational models and simulations were performed to assess the cellular effects of the R76C mutation. The simulated ICC slow wave was decreased in duration and the resting membrane potential in the SMC was depolarized. Thus, the R76C mutation was sufficient to alter ICC and SMC cell electrophysiology. However, the cause-effect relationship between R76C and intestinal pseudo-obstruction remains an open question.
[Show abstract][Hide abstract] ABSTRACT: Gastrointestinal (GI) motility is coordinated by several cooperating mechanisms, including electrical slow wave activity, the enteric nervous system (ENS), and other factors. Slow waves generated in interstitial cells of Cajal (ICC) depolarize smooth muscle cells (SMC), generating basic GI contractions. This unique electrical coupling presents an added layer of complexity to GI electromechanical models, and a current barrier to further progress is the lack of a framework for ICC-SMC-contraction coupling. In this study, an initial framework for the electromechanical coupling was developed in a 2-D model. At each solution step, the slow wave propagation was solved first and [Ca(2+)](i) in the SMC model was related to a Ca(2+)-tension-extension relationship to simulate active contraction. With identification of more GI-specific constitutive laws and material parameters, the ICC-SMC-contraction approach may underpin future GI electromechanical models of health and disease states.
[Show abstract][Hide abstract] ABSTRACT: Gastrointestinal (GI) motility disorders are not well understood, resulting in patient management that typically controls symptoms. Patients suffer from reduced quality of life and incur large costs from chronic GI disorders. It is imperative to elucidate underlying mechanisms causing GI motility disorders that, in turn, can facilitate development of treatment such as drug therapeutics. To this end, we seek to use multi-scale computational models to better understand GI motility in health and disease. An initial computational framework was established to study genetic perturbation in causing a phenotypical change at the GI tissue level. Computer models describing a couple of genetic perturbations were developed and examined in the multi-scale framework. Preliminary findings suggest alterations to phenotype that may adversely affect GI motility. However, much work remains, given the tissue complexity and uncertainties in our knowledge of the GI organs. A future direction will be to incorporate multi-scale mechanical models in the current framework.
Conference proceedings: ... Annual International Conference of the IEEE Engineering in Medicine and Biology Society. IEEE Engineering in Medicine and Biology Society. Conference 08/2011; 2011:429-32. DOI:10.1109/IEMBS.2011.6090057
[Show abstract][Hide abstract] ABSTRACT: The muscular layers within the walls of the gastrointestinal tract contain two distinct cell types, the interstitial cells of Cajal and smooth muscle cells, which together produce rhythmic depolarizations known as slow waves. The bidomain model of tissue-level electrical activity consists of single intracellular and extracellular domains separated by an intervening membrane at all points in space and is therefore unable to adequately describe the presence of two distinct cell types in its conventional form. Here, an extension to the bidomain framework is presented whereby multiple interconnected cell types can be incorporated. Although the derivation is focused on the interactions of the interstitial cells of Cajal and smooth muscle cells, the conceptual framework can be more generally applied. Simulations demonstrating the feasibility of the proposed model are also presented.
[Show abstract][Hide abstract] ABSTRACT: Interstitial cells of Cajal (ICC) isolated from different regions of the stomach generate spontaneous electrical slow wave activity at different frequencies, with cells from the proximal stomach pacing faster than their distal counterparts. However, in vivo there exists a uniform pacing frequency; slow waves propagate aborally from the proximal stomach and subsequently entrain distal tissues. Significant resting membrane potential (RMP) gradients also exist within the stomach whereby membrane polarization generally increases from the fundus to the antrum. Both of these factors play a major role in the macroscopic electrical behavior of the stomach and as such, any tissue or organ level model of gastric electrophysiology should ensure that these phenomena are properly described. This study details a dual-cable model of gastric electrical activity that incorporates biophysically detailed single-cell models of the two predominant cell types, the ICC and smooth muscle cells. Mechanisms for the entrainment of the intrinsic pacing frequency gradient and for the establishment of the RMP gradient are presented. The resulting construct is able to reproduce experimentally recorded slow wave activity and provides a platform on which our understanding of gastric electrical activity can advance.