Developing 3D models of blood vessels for drug discovery
Principal Supervisor: Dr John SimmsLink opens in a new window
Co-supervisor: Dr Dan Rathbone
PhD project title: Developing 3D models of blood vessels for drug discovery
University of Registration: University of Aston
Project outline:
Cardiovascular disease including hypertension, stroke, aneurysms, and peripheral artery disease affects 6 million people in the UK and is a major cause of health inequality. Whilst changing lifestyles is key to prevention, our understanding of the progression of many of the diseases associated with the cardiovascular system has stalled through the lack of good in vitro models.
Two-dimensional (2D) cell culture has often been used to understand the progression of disease. However, increasingly, 2D, in vitro, cell culture-based, models have led to misleading results when compared to in vivo data. Culturing cells in three dimensions using hydrogels and other extracellular mimetics has generated results that correlate well with similar studies performed in tissues. In parallel to the advances in cell culture, biocompatible materials in combination with 3D printing has enabled the production of devices capable of simulating either “native-like” or pathophysiological conditions. Conventional methods to develop these devices (popularly referred to as ‘Organs on a Chip’) are still in their infancy, but heart, kidney, bone and cartilage mimics have been successfully developed. These systems have a range of advantages over current cell culture methods, especially in fields such as drug discovery and regenerative therapies. Also, the chips can be designed to aid biomolecular characterisation and can be used to explore the biochemistry of important classes of drug targets such as membrane proteins and their lipid environment.
Previous work in the lab has highlighted that sheer stress on 3D cell culture models of blood vessels selectively influences intracellular signalling pathways. Considering the signalling bias observed in cardiovascular therapeutics coupled with the intracellular changes caused by a cells physical environment these collectively may impact on how patients are ultimately treated. The aim of this project is to generate multi-layered 3D models of blood vessels to understand, at the molecular level, how physical phenomena such as flow, sheer stress, local and global pressure changes, nutrients etc influence cellular biology and membrane protein pharmacology. These data will then be used to generate a molecular model of how changes in the membrane are then able to influence the activity of membrane proteins including GPCRs.
There will be a wide range of skills taught as part of this PhD programme and will include 3D cell culture, 3D printing, Pharmacology, Fluidics, Molecular Biology, Biophysics and Computational Biology.
BBSRC Strategic Research Priority: Understanding the rules of life - Structural Biology, and Integrated Understanding of Health - Ageing
Techniques that will be undertaken during the project:
There will be a wide range of skills taught as part of this PhD programme and will include 3D cell culture, 3D printing, Pharmacology, Fluidics, Molecular Biology, Biophysics and Computational Biology.