Why did we fund this fellowship?
This award aims to develop a computational model to study the mechanical role of the extracellular matrix (ECM) in tissue development and function replacing mammalian model organisms, such as rats and mice.
Dysregulated ECM composition, both during early development and later in life, can result in various pathological conditions such as Alport’s syndrome, fibrosis and kidney failure. Animals are used in basic research studies to further understanding of the ECM and to provide insights into disease. The development of the ECM is perturbed in some of these studies, either by genetically modifying the animal to introduce a relevant mutation or by treating the animal with a chemical such as small molecule inhibitors. In vitro methods in ECM research do exist but these require animal-derived matrices, for example Matrigel is often used to provide structural support to 3D organoid cultures used in the research. Dr Nargess Khalilgharibi will build upon work from her supervisor, Dr Yanlan Mao, to develop a computational platform to study the mechanical role of the ECM in shaping and maintaining tissue architecture, helping to replace some rodent studies in this area.
During her Fellowship, Nargess will use this experience to adapt the model to make it applicable to tissues with different structures and properties as well as organoid growth and function. To better enable uptake, Nargess will publish the model with a user-friendly graphical user interface. She will develop skills in quantitative imaging, organoid culture and further expand her computational modelling capabilities.
The tissues in the body are lined by the extracellular matrix (ECM), a meshwork of proteins that acts as a physical support and provides them with biochemical and mechanical cues. Cells have the ability to change the composition and mechanical properties of the ECM through synthesis, degradation and rearrangement of its components. These changes are crucial for developing flat sheets of tissues into complex 3-dimensional structures. In adult life, correct ECM composition is vital for maintaining tissue shape and ensuring its correct function. Dysregulation in ECM composition and mechanical properties, either during development or later in life and as a result of disorders such as diabetes, can lead to severe pathological condition, such as kidney failure, hearing loss and blindness.
So far, most of the knowledge about the role of ECM in tissue growth and function has come from animal experiments. However, it is still not possible to follow live changes in ECM structure and composition in the same animal. Therefore, a single study looking at these changes, either through a developmental process or during disease progression, requires sacrifice of many animals. Recently, scientists have been trying to grow organ-like tissues (i.e. organoids) in the lab. These organoids have high clinical potential and can replace animal research in the fields of tissue development and disease. However, majority of current organoid culture techniques rely on the use of extracellular matrix scaffolds derived from animals, which affects their reproducibility and hinders their translation into clinics. Scientists are working to replace these animal-derived matrices with synthetic ones, a process that requires large amount of time and resources.
I propose to develop a multiscale computational platform of tissue growth and function, with explicit implementation of the extracellular matrix mechanics. This will allow researchers to model the growth of their tissue of interest, test the effect of different conditions on its growth and function, and design a minimum set of experiments to carry out in the lab, therefore replacing many animal experiments with computer simulations. The model will also allow researchers to simulate growth of organoids in synthetic matrices with different mechanical properties, and identify the optimal properties that can be further fine-tuned experimentally. This will significantly enhance protocol optimisation steps, allowing researchers to easily tailor-design synthetic ECM matrices for growth of different organoids, and eventually fully replace animal matrices with their synthetic counterparts. Finally, the open-source nature of our model will also allow researchers to incorporate their data into the model to capture more sophisticated processes, and therefore significantly reduce animal use.
Khalilgharibi N & Mao Y (2021) To form and function: on the role of basement membrane mechanics in tissue development, homeostasis and disease. Open Biology 11(2): 200360 doi: org/10.1098/rsob.200360