Last September, the first annual PRiME Fellowship Awards were presented to 10 outstanding trainees at the University of Toronto to drive forward high-risk, multidisciplinary research focused on solutions in precision medicine. Projects ranged from innovations in drug discovery to diagnostic development and improving our understanding of disease biology. As we approach the end of our first funding round, we provide a closer look at the 2019 PRiME Fellows’ year of scientific progress and success, and a preview of the exciting work that still lies ahead for these researchers.
Dr. Noor Al-saden’s project proposed to develop radiation therapy using gold nanoparticles that delivers radionuclide straight to brain tumour cells for local treatment of a fast-growing brain cancer, glioblastoma multiforme (GBM). Under the supervision of radiation nanomedicine specialist Prof. Raymond Reilly (Leslie Dan Faculty of Pharmacy) and polymer chemist Prof. Mitch Winnik (Faculty of Arts & Science), Noor has been constructing and characterizing these gold nanoparticles and began testing how effective they are in killing GBM cells in vitro. She also plans to test her therapy in mice to determine the ability of the nanoparticles to selectively kill tumour cells while leaving normal brain cells unharmed. Preliminary results from Noor’s work led to a $200,000 Canadian Cancer Society Innovation Grant awarded to Prof. Reilly’s group, for a project using radiation nanomedicine therapy in combination with current checkpoint immunotherapy for intraoperative treatment of GBM.
Dr. Rony Chidiac has been studying how Frizzled (FZD) signaling affects the permeability of the blood-brain or retinal barrier (BBB/BRB), which can deteriorate or become dysregulated in neurodegenerative disorders and retinal disease. In the past year, Rony brought together expertise in Wnt/FZD signalling from the lab of Prof. Stephane Angers (Leslie Dan Faculty of Pharmacy) with the antibody engineering knowledge of Prof. Sachdev Sidhu (Faculty of Medicine) and investigated the activation of FZD4 signaling in endothelial cells using a novel antibody-based FZD4 agonist. Next, Rony expects to test the effects of FZD4 signaling in primary endothelial cells as well as in a mouse model.
Angela Duong has been working to understand mitochondrial function and its role in neuronal activity in the laboratory of Prof. Ana Andreazza (Faculty of Medicine). With guidance and expertise from Profs. Liliana Attisano and Martin Beaulieu (both Faculty of Medicine), Angela has grown 3D in vitro cultures of brain cells (cerebral organoids) from human induced pluripotent stem cells. This was done by reversing patient blood cells into a stem cell state, and then generating cerebral organoids. She has characterized the different cell types growing in these organoids and measured the electrophysiological activity of the neurons. Additionally, she has been studying the state of the mitochondria over the course of cell differentiation and plans to examine its function in these cells by selectively knocking down or inducing different mitochondrial genes in the system.
Dr. Margot Karlikow has proposed to use gold nanoparticles to establish a sensing tool that can detect if pathogen genetic material is present in a sample. The presence of a pathogen would activate the gene-editing CRISPR tool to make DNA breaks within nanomaterials that can be detected optically. This project combines the expertise of Prof. Keith Pardee (Leslie Dan Faculty of Pharmacy) in synthetic biology with that of Prof. Gilbert Walker (Faculty of Arts & Science) in nanomedicine. Margot has already worked out a fluorescent-reporting system that senses DNA breakage and constructed the gold nanoparticle that captures the released DNA to facilitate this output. She is currently working to put all of this together and then will validate the effectiveness of this device.
Anastasia Korolj’s project aimed to diagnose recurring kidney disease after transplantation by looking at patient serum samples in a dish. Under the guidance of Prof. Milica Radisic and Prof. Axel Guenther (both Faculty of Applies Science & Engineering), Anastasia has been designing a device that contains podocyte cells which change morphology when exposed to patient samples with signs of disease. She is currently optimizing this platform and testing to validate its effectiveness in patient samples with help from Dr. Ana Konvalinka (Faculty of Medicine). The foundational work that Anastasia did as a PRiME Fellow has led to follow-on funding from NSERC and CRAFT of $150,000.
Dr. Jiabao Liu has spent the past year identifying and investigating high affinity, fatty acid binding partners for PPAR orphan receptors to understand how to better treat PPAR-related diseases. Using a myriad of approaches from metabolomics to de novo synthesis, chromatography, and circular dichroism, Jiabao was able to characterize selective ligand targets, their binding stability, and their role in neuronal function. His research contributed to a successful New Frontiers in Research Funding (Exploration) grant for $250,000 worth of funding for supervisors Profs. Henry Krause (Faculty of Medicine) and Carolyn Cummins (Leslie Dan Faculty of Pharmacy), and collaborator Prof. Hui Peng (Faculty of Arts & Science).
Dr. Mark Mabanglo sought to understand how small molecules can interact to inhibit the ClpP protease in bacteria to become effective antibiotics. Working in the laboratory of Prof. Walid Houry (Faculty of Medicine), with guidance in organic chemistry from Prof. Robert Batey (Faculty of Arts & Science), Mark grew crystals of ClpP and validated its activity in this state. Furthermore, Mark has collaborated with the labs of Drs. Peng Chen and Chu Wang at Peking University in China to design mutant variants that can be used in future studies to determine how the protein folds and functions.
Dr. Jiaxi Peng proposed to investigate the profile of proteins expressed by neural stem cells during aging. He has developed a digital microfluidics/laser-cell lysis system to accomplish this and was able to optimize its use to produce sensitive results at the single cell level at low sample concentrations. This project merged the expertise of Prof. Aaron Wheeler in microfluidics and single cell analysis with that of Prof. Hui Peng in high-resolution mass spectrometry and proteomics (both Faculty of Arts & Science). He is now using this system to better understand neurodegeneration in Huntington’s and Alzheimer’s disease.
Yuxi Xiao’s project aimed to develop a tool for studying the function of multiple genes in a high-throughput manner. Under the supervision of Prof. Jason Moffat (Faculty of Medicine), she has been establishing a pooled screening protocol using the CRISPR-Cas12a gene editing system. She has designed and performed a pilot screen to identify gRNA characteristics that result in successful gene targeting. Combined with microfluidics, with help from Prof. Shana Kelley (Leslie Dan Faculty of Pharmacy), Yuxi will continue to increase the speed and throughput of this assay to study gene interactions. The Kelley-Moffat project recently led to a UofT-industry collaboration that will bring additional resources to this effort.
Dr. Fei Xu has been developing an in vitro small-molecule drug screen using a microfluidics platform and artificial intelligence. Under the guidance of Prof. Eugenia Kumacheva (Faculty of Arts & Science), Fei has grown cancer cells on a hydrogel that can be held in three different microfluidics prototype devices that she has developed. She is currently optimizing this platform in order to determine how effective different anti-cancer drugs are in killing breast cancer cells. With expertise from Prof. Alan Aspuru-Guzik (Faculty of Arts & Science), she plans on using AI to analyze the results and further adapt her device to accommodate testing of other cell types and drug formulations. Fei’s work contributed to a successful application to the New Frontiers of Research Fund (NFRF) Exploration program resulting in a $200,000 grant to Prof. Kumacheva’s group.
Even with the unprecedented pause in research due to COVID-19, we are proud of the significant progress our Fellows have been able to achieve within this year of support from PRiME. We are looking forward to announcing the 2020 PRiME Fellows in September. With the wealth of talent here at the University, we have no doubt that the next cohort of awardees will bring equally exciting ideas and discoveries to precision medicine.