IU researchers visualize better treatments for eye disease

Thanks in part to the mishandling of donated human retina during shipping, researchers have developed detailed computer simulations that enabled them to uncover a previously undetected mechanism that causes choroidal neovascularization of the macular area of the retina

Amy Swinderman
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BLOOMINGTON, Ind.—Thanks in part to the mishandling ofdonated human retina during shipping, a research group based at IndianaUniversity (IU) has developed detailed computer simulations of the behaviorsand interactions of the cells and membranes composing the rear of the retina,enabling them to uncover a previously undetected mechanism that causes choroidalneovascularization (CNV) of the macular area of the retina, the major cause ofsevere vision loss in adults.
 
 
CNV is the creation of new blood vessels in the choroidlayer of the eye. This is a common symptom of the degenerative maculopathy wetage-related macular degeneration (AMD), a condition that causes vision loss dueto abnormal blood vessel growth in the choriocapillaris, ultimately leading toblood and protein leakage below the macula. Bleeding, leaking and scarring fromthese blood vessels eventually cause irreversible damage to the photoreceptorsand rapid vision loss if left untreated.
 
 
Current treatments for CNV either kill the invading bloodvessels with drugs injected into the eye—also damaging the retina and killingneeded blood vessels—or laser-heat the blood vessels, which can cause damagingretinal scars. Abbas Shirinifard, a postdoctoral research her in IU'sBiocomplexity Institute and senior author on a paper recently published in PLOS Computational Biology, observes that adecade's worth of research—and the publishing of approximately 9,000 researchpapers on CNV—notes that current available treatments fail to address theunderlying problems that cause the blood vessels to invade.
 
 
"Many patients still lose vision within a year or two," saysShirinifard. "Since these therapies wait until the blood vessel invade andstart to deteriorate the retina, therapies for CNV are only good after thefact. In our computational model, we found that the main causes of thisinvasion are not really the ones these drugs are designed for."
 
 
But how Shirinifard and his colleagues came to develop thatcomputational model is an interesting story in itself. An accident during theshipment of donated human retina from an eye bank caused regions of the retinawith invading blood vessels to separate from their underlying membranes, whileregions that stayed attached showed much less invasion. This suggested thatadhesion might be an essential—but overlooked—mechanism in maintaining theretina's structure.
 
 
"The container had some air bubbles in it, and the packagewas thrown. I thought I wasn't going to get anything out of it, but some piecesof the tissue were still attached, and I could use them to make somemeasurements," explains Shirinifard. "After that accident, we began lookingmore into how the retina forms during development, and how important adhesionis in that tissue.
 
 
This inspired Shirinifard to design a series of newsimulations.
 
 
"We synthesized our own hypothesis, which was that adhesionfailures are enough to explain both initiation and pattering in CNV," he says.
 
 
Using an open-source modeling software program calledCompuCell3D developed by the Biocomplexity Institute in collaboration with theUniversity of Washington and the University of Wisconsin under NationalInstitutes of Health funding, the team began extending existing simulations tostudy the effects of adhesion defects. The team soon discovered that threeprominent types of adhesion play a role: between the pigmented retinal cells(the black lining of the eye) and Bruch's membrane (the substrate that supportsthe retina), between adjacent pigmented retinal cells; and between pigmentedretinal cells and the overlying photoreceptors. These variables, theresearchers discovered, could either be independent of each other or interactin complex ways, and thus determine the probability, rate and progression ofCNV.
 
 
"We were able to model the interactions of different degreesof impairment of each type of adhesion and the variation from case to case,"Shirinifard says. "Amazingly, these simulations were able to replicate thecomplex spectrum of CNV seen in the clinic."
 
A 3D video of Shirinifard's work can be seen here:
http://www.indiana.edu/~iunews/flash/videos/Type1_combine.mp4.
 
 
The work should have great significance in the search forbetter therapies for CNV, but the results could also have a much broaderimpact, says Shirinifard.
 
 
"Surprisingly, a simple theory based on classes of adhesionfailures, which involve variation of only five parameters, can coherentlyexplain the heterogeneous range of CNV growth patterns and dynamics," he says. "Ourresults are generally applicable to other types of tissues where capillariesare close to an epithelium, e.g., thelung and gut. The relationships between specific classes of adhesion failuresand the types and dynamics of CNV in the eye simulations should carry over tothe neovascularization-dependent pathologies of those tissues and to invasionof those tissues in cancer progression."
 
 
The study, "Adhesion Failures Determine the Pattern ofChoroidal Neovascularization in the Eye: A Computer Simulation Study," waspublished in the May 2012 issue of PLOSComputational Biology. Shirinifard's colleagues on the study included JamesAlexander Glazier, Maciej Swat and J. Scott Gens of the Biocomplexity Instituteand Department of Physics at the Indiana University Bloomington; the FereydoonFamily of the Department of Physics at Emory University, Yi Jiang of theDepartment of Mathematics and Statistics at Georgia State University and theLos Alamos National Laboratory; and Hans E. Grossniklaus of the L.F. MontgomeryOphthalmic Pathology Laboratory at Emory University. 



Amy Swinderman

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