Grant: Discovery Grants Program - Individual

My research program is focused on development of magnetic resonance imaging (MRI) of reporter genes (RGs) as a tool for non-invasive detection of implanted cells. Prior to implantation, cells are engineered to express a cell membrane transporter. This protein allows the cells to preferentially take up and retain an MRI contrast agent producing enhanced MR signal making them stand out compared to surrounding tissues. This provides 3D information of the distribution of only viable implanted cells along with images of surrounding anatomy that is the hallmark of MRI. Recently, we have demonstrated the ability of our reporter gene imaging (RGI) technology to detect as few as 1000 cells in mice. In this research program, we are working to reduce this detection limit through significant improvements in contrast agents, cellular uptake, RF detection hardware and imaging protocols. This interdisciplinary research provides broad training in diverse fields from MR imaging science, synthetic biology, chemistry, and RF engineering through established collaborations with other research groups whose expertise spans this entire space. Use of RGs to track implanted cells allows researchers to determine their location, number, and activity without having to sacrifice many groups of animals at a series of time points for histological examination. This reduces the number of animals for research and greatly improves the quality of the experimental results, as the effects of the implanted cells can be observed over time in the same animal. Other technologies, such as bioluminescence imaging (BLI) have been used for cell tracking, but smaller cell populations such as metastases can be hard to detect when near larger primary tumours. Although BLI is more sensitive than RGI with MR, it does not provide high-quality 3D anatomical images. Trainees will work on several fronts to improve the sensitivity of our MRI RG technology so that it approaches BLI. We will evaluate increased expression of our RGs to assess any unexpected effects on cell biology. Trainees will measure the relaxation properties of new contrast agents based on manganese and assess utility for RGI. This will be done through cell uptake experiments, with the most promising results assessed in mice. We will iterate this process with our chemists to achieve the best combination of MR relaxivity, cellular uptake, and reduced toxicity so these agents can be used at higher doses in animals. Finally, trainees will construct improved MRI RF hardware for mouse imaging and optimize pulse sequences for acquisition of RG images. As we develop new precision medicine involving cell- and gene-based therapies, there is an urgent need to develop molecular imaging tools to monitor their delivery and presence at disease sites and to determine off-target effects. We believe that, when fully optimized, this RGI technology will have the sensitivity to provide this information for assessing treatment of human disease.