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Intercellular Permeation of Macromolecules
Molecules of size ~1 nm play an important role in signal
transduction pathways inside cells as well as in intercellular coupling.
The rate of permeation of these molecules through intercellular pathways
(gap junctions) is an important parameter that sets the scope of
coordinated tissue function. For example, in sparsely innervated tissue
(e.g. large vascular vessels), gap junctional communication acts a
conduit for the propagation of neuronally stimulated input to the rest
of the non-innervated tissue. This mechanism of coordination also
applies in tissues (e.g. pancreatic islets) where cells directly
influenced by hormones and metabolites from the blood stream would
influence cells remote from these agents. We are studying the influence
of the nature of the diffusing agent as well as the nature of the gap
junction channels on the permeation mechanism. Elucidating the
mechanism may have an impact in understanding the role of permeating
agents in suicide gene therapy.
Macromolecular Permeation through Nanopores
Biological polymers of cross-section 12A can permeate various biological pores of dimension 15A and above. The permeability of such molecules is approximately 1/1000 of that of ions. Various groups have shown that, when ssDNA permeates hemolysin channels, the ion flow across the channel is interrupted. The hope is that specific changes in the current level can be correlated to the nature of the particular chemical moiety traversing the narrow part of the channel. We are examining gap junctions channel (15A) and porins (15-20A) in this context. Particular circumstances (slow gating, poor voltage dependence of gating and other related biophysical characteristics) make these channels particularly good candidates for studying DNA translocations and interactions.
Intercellular coupling i.e. coupling of intracellular biochemical pathways plays an important role in syncyctial coordination. We are developing a quantitative understanding of the role of intercellular gap junction communication in tissue function. We are currently modeling the steady state response of a single vascular smooth muscle (VSM) cell. This model will be integrated into a scheme for syncytial coordination, where intercellular pathways for the flow of ions and larger macromolecules will be linked to intracellular second-messenger pathways. We are also collaborating with Dr. Christ (Albert Einstein College of Medicine) on models of arterial smooth muscle where both calcium sparks and calcium waves play a role in vasoconstriction through different calcium-release mechanisms. The Center already has a 8-machine Beowulf cluster for molecular modelling, and the algorithms for intercellular coordination will be parallelized using the PVM/MPI message passing model. When the number of modelled cells in a tissue increases to the envisaged 10000, distributed algorithms currently offer the only cost-effective way to reduce execution times.
Information Extraction from the
The Center has a computational linguistic group; members of this group are collaborating with biologists to develop novel ways of extracting useful information from published biological literature (such as the Medline Abstracts) using Natural Language Processing (NLP) tools and techniques.
This is still incomplete.
Life Sciences Division, AU-KBC Research Center
MIT, Chromepet, Chennai 600044
(tel) +91-44-2-223-4885 (fax) +91-44-2-223-1034