Interview: Lazarina Gyoneva


Lazarina Gyoneva is a graduate student in the research group of Professor Victor Barocas (MSI Fellow; Biomedical Engineering). She came to the University of Minnesota as a grad student in 2010 and started using MSI resources in the spring of 2011. Ms. Gyoneva was a finalist in the poster competition at the 2013 MSI Research Exhibition with her poster, “Role of Lateral Interactions in Collagen IV Network Mechanics.” Other MSI PIs who were co-authors on this poster are Yoav Segal (Medicine) and Kevin Dorfman (Chemical Engineering and Materials Science). Ms. Gyoneva sat down with MSI recently to discuss her work.

MSI: What do you use MSI for?

Lazarina Gyoneva: On the computational side, I use mostly the different C++ compilers and MATLAB, and on the analytical side, I use statistical and graphical packages like GraphPad Prism and SAS. I use them through the labs.

MSI: Your poster describes type IV collagen. Can you explain the difference between collagen IV and the kind of collagen we’ve all heard about in the skin?

LG: There are actually over 20 different types of collagen, all products of different genes. The collagen found in skin is type I. Type IV collagen is the type that’s present in basement membranes – the part of the extracellular matrix on which epithelial cells are attached. Type IV collagen is slightly different from type I collagen in its molecular structure and organization. Because of their differences in molecular structure and processing, type I collagen is able to form thick strong fibers while type IV collagen molecules can’t be packed closely enough to form fibers and they self-organize into planar networks.

There are three known kinds of collagen IV. The two most common ones are the so-called “major” and “minor” kinds, and even between them there are differences based on primary and secondary structures of the proteins.

MSI: What are you trying to do in this poster?

LG: We are looking at the role of lateral interactions on the mechanical properties of type IV collagen networks. The two different types of collagen IV, the major and the minor, are believed to have different abilities to form lateral interactions, therefore they can form slightly different networks. The minor chains also have the ability to wind around each other, forming “supercoils,” which probably changes the structure of the network as well as the mechanical properties of the network.

So, we already see that they have some structural differences, and we wanted to know how these structural differences could affect the mechanical properties. The reason we’re interested in that is because, clinically, we know that the minor chains are vital for the proper functioning of the collagen networks of the kidneys and the lens of the eye. When the minor chains are missing from those locations [Ed: a condition called Alport Syndrome], the collagen networks cannot perform their mechanical functions in those locations. We want to know what properties of the minor chains make them so vital.

MSI: How did you use MSI?

LG: We generated networks in MATLAB that represent the major and minor collagen networks. The generated networks have the same connectivity and relative concentrations as the physiological collagen IV networks. We introduced lateral interactions in the minor chain networks constraining the networks a little bit more. In some places, we created “supercoils,” to which we assigned double the stiffness and double the cross-sectional area of normal chains. We then took the generated networks and simulated their mechanical deformation to obtain their stress-strain response. The mechanical simulations are done with a force-balance code in which the boundaries of the networks are stretched first, then all internal segments are allowed to move around until they are in a position at which the sum of the forces on each chain is zero. From the force calculations, we can also calculate the stresses that are applied to these networks.

We generated two different networks, one (kidney) with a higher percentage of minor chains, and another (lens) with a lower percentage of minor chains and we tested what happens when we increase the connectivity of the minor chains.

MSI: Does this research have immediate applications, or is it more basic science?

LG: It’s definitely more on the theoretical side. The main reason we think it’s important to look at this is because not much is known about the mechanical role of the minor chains and what are the primary causes for the disturbances seen in Alport Syndrome when the minor chains are absent. We believe that Alport Syndrome may be caused by a loss of mechanical functionality, initiating a number of secondary biological responses. Current treatments have focused on the biological side but it’s very important to learn more about the primary causes so we can discover ways to treat the diseases earlier.

MSI: Will this eventually have applications for clinical treatment?

LG: I can’t speak yet of direct clinical applications, but what we are learning about the importance of network structure for mechanical properties could have applications not just for Alport Syndrome, but for material science in general. The ability to build biological or synthetic networks that can be easily modified to adjust their mechanical properties would be very desirable.

MSI: How much more needs to be done with this project?

LG: There are definitely a lot of unanswered questions in this area. The networks generated for the simulations are idealized representations. Ideally, we would like to have ultra-high resolution Scanning Electron Microscopy images of actual lens and glomerular basement membranes from which we can extract the exact topology of collagen IV networks. Then we can digitize the real networks and use them for the mechanical stretching simulations. There are some other things that we can look at. For example, we still don’t know how exactly the minor and major chains interact with each other, how they are distributed in basement membranes, if the higher number of cysteines really corresponds to a higher number of lateral interactions, or what is it about the minor chains that makes them form supercoils when the major chains don’t do that. Those are all basic questions that need to be answered.

MSI: Do you make the models using information that you got experimentally?

LG: Some of the parameters used in the computational model are taken from literature on collagen IV and collagen I. We did perform a set of experiments last year that were very informative in quantifying the importance of the minor chain network in contributing additional strength to the basement membrane of the ocular lens. One of the purposes for this computational project was to try to explain some of the experimental results where we used wild-type and Alport mutant mouse lenses and compared their distensibility. We saw that when the minor chains are missing, the lens is much more compliant. This computational study is now trying to explain what it is about the minor chain that gives them additional mechanical strength.

posted on July 31, 2013

See all Research Spotlights.