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SUMMARY:Towards a Colonic Crypt Model with Realistic\, Deformable Geometry
  - Sara-Jane Dunn\, University of Oxford
DTSTART:20110411T101500Z
DTEND:20110411T111500Z
UID:TALK30735@talks.cam.ac.uk
CONTACT:Microsoft Research Cambridge Talks Admins
DESCRIPTION:Colorectal cancer (CRC) is one of the leading causes of cancer
 -related death worldwide\, demanding a response from scientists and clinic
 ians to understand its aetiology and develop effective treatments. CRC is 
 thought to originate via genetic alterations that cause disruption to the 
 cellular dynamics of the crypts\nof Lieberk¨uhn\, test tube shaped glands
  lined with a monolayer of epithelial cells\, which responsible for renewi
 ng the intestinal surface through a coordinated sequence of cell division\
 , migration and death. It is believed that in the first step of colorectal
  carcinogenesis\, crypts acquire genetic mutations that disrupt the normal
  patterns of cell proliferation and migration\, which can lead to crypt bu
 ckling and fission\, and the formation of a benign tumour. Over time and v
 ia accumulated mutations\, these growths progress to a malignant lesion th
 at can break through to the underlying tissue stroma\, and so aid metastas
 is. The dynamic cell properties that are required to initiate crypt buckli
 ng are poorly understood\, as it is difficult for biologists to experiment
 ally observe\, either in vivo or in vitro\, the initial changes in this se
 quence of events. Performing in silico experiments using an accurate\, pre
 dictive computational model of the crypt can identify the key changes and 
 responsible mechanisms. Such a model must account for the tissue structure
 \, incorporating the elements that provide stability\, without imposing a 
 fixed shape. In particular\, the role of the basement membrane is vital in
  maintaining the integrity and structure of the epithelial monolayer\, act
 ing as both a mechanical support and forming the physical interface betwee
 n epithelial cells and the surrounding connective tissue. \n\nA model is p
 roposed here to directly address these criteria. An off-lattice cell-centr
 e modelling approach is adopted\, with cell-cell connectivity defined by a
  Delaunay triangulation\, and polygonal cell shapes realistically prescrib
 ed by the dual Voronoi tessellation. A novel method for modelling the role
  of the basement membrane beneath a growing epithelium is presented\, whic
 h subsequently allows the desired crypt geometry to develop. Further to th
 is\, the model takes into account the continuous meshwork of actin that fo
 rms a basket below each crypt base\, and which provides stability to this 
 region. Results from in silico simulations show that homeostasis of the gr
 owing epithelial monolayer can be achieved and sustained within this model
 ling framework\, and the necessary balance of interactive cell forces\, ce
 ll migration and cell death are presented.\n\nThe computational framework 
 for this model is based within the Chaste environment (http://www.comlab.o
 x.ac.uk/chaste/)\, an open source software library written in object-orien
 ted C++. Chaste is a general purpose simulation package aimed at multi-sca
 le\, computationally demanding problems arising in biology and physiology\
 , developed using agile programming techniques and following software engi
 neering practices. The modular nature of the Chaste framework enhances mod
 el versatility – it is possible to apply and compare alternative cell in
 teraction models\, cell cycle models and tissue geometry. As a key compone
 nt of the proposed crypt model\, this computational modelling framework wi
 ll be introduced.\n\nThis model is proposed as the foundation of a realist
 ic representation of growth of an epithelial sheet in a deformable environ
 ment\, and forms the basis for investigation of the deformation of the cry
 pt structure that can occur due to proliferation of cells exhibiting abber
 ant\, mutant phenotypes. Whilst it is applied here specifically to the col
 onic crypt\, the basic principles extend to other biological epithelia\, s
 uch as the interfollicular epidermis\, or the olfactory mucous membrane. T
 hus\, this work and the results presented\, hold potential for future rese
 arch in other biological contexts.\n
LOCATION:Large lecture theatre\, Microsoft Research Ltd\, 7 J J Thomson Av
 enue (Off Madingley Road)\, Cambridge
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