2020 New Ideas and Seed Fund Awards

Lead Investigator:

Leo Chou
Institute of Biomedical Engineering, University of Toronto

Co-Investigators:

Julie Lefebvre
The Hospital for Sick Children

Valerie Wallace
Krembil Research Institute, University Health Network

Project Description: Cell transplantation is being widely developed as a promising treatment for dysfunctional tissues, especially for those with restricted capacity for endogenous repair. In the context of the retina, cell transplantation has demonstrated encouraging pre-clinical results, including partial vision restoration in several animal disease models. While functional restoration was originally seen as evidence of physical integration between donor cells and host tissue, recent studies have demonstrated substantial transfer of key proteins between these cells, not integration, as a primary outcome of photoreceptor transplantation. Despite the emerging role of material transfer in cell transplantation,  the scope of the transfer process is still not understood, including the extent, subcellular localization, and diversity of the cargo. This project will develop a high throughput, single-molecule imaging approach to detect the transfer of endogenous mRNA molecules between donor and host cells, which will accelerate but not duplicate ongoing studies. The novelty is the design of imaging probes that distinguish highly similar mRNA isoforms in human-mouse and mouse-mouse co-cultures and transplant models. This approach will allow the investigators to assess intercellular mRNA transfer efficiency, distribution, and kinetics for a curated library of endogenous transcripts. This project will also test whether intercellular mRNA transfer can be leveraged to deliver therapeutic protein cargo and restore tissue function. The outcomes from this project will inform future design of cell transplantation therapies and lead to novel method to deliver therapeutics. These efforts have the potential to ameliorate retinal diseases and visual impairments and can inform strategies for other degenerative disorders.

Lead Investigator:

Hyun Kate Lee
Biochemistry, University of Toronto

Co-Investigator:

Penney Gilbert
Institute of Biomedical Engineering, University of Toronto

Project Description: All of our daily movements, including breathing, require healthy connections and signaling between motor neurons and muscles. Neuron-muscle communication throughout our bodies is mediated via a common structure called the neuromuscular junction (NMJ). Defects in NMJ integrity and function underlie fatal diseases such as Amyotrophic Lateral Sclerosis and Spinal Muscular Dystrophy. Though NMJ diseases affect over a half million people globally, effective treatments or cures are currently lacking.

It is not well understood how the human NMJ is built and maintained. Thus, understanding the cell biology of the human NMJ in health and in disease is an essential first step toward developing targeted therapeutic approaches. This project aims to develop new tools and knowledge to address these questions. Using iPSCs derived from reprogrammed skin cells of healthy persons, the investigators will develop human neuromuscular junctions in 3D culture. Using quantitative hi-resolution imaging techniques, the investigators will define key characteristics of the cellular architecture and operation of the healthy human NMJ synapse. The investigators will then determine how the process of synapse formation, maturation, and function is perturbed across different ALS patients by examining NMJs built from patient cells. Finally, the investigators will define the involvement of a protein quality control regulator they found to be downregulated in ALS neurons on NMJ health. These findings will allow the investigators to identify candidate genes to target and improve the health of the diseased NMJ synapse in follow-up studies, for example by preventing or delaying NMJ degeneration or by promoting NMJ repair and regeneration.

Lead Investigator:

Amy Wong
The Hospital for Sick Children

Project Description: Cystic Fibrosis (CF) is a common genetic disease which causes difficulties in breathing, recurrent lung infections and death. Current drug treatments aimed at targeting the genetic defect cost $300,000 CAD/year and is not a viable economical and treatment option for most CF patients, therefore continued efforts to find a cure for CF is imperative.

The team developed the first human lung epithelial cells in the petri dish derived from pluripotent stem cells (PSC). When generated from PSC harbouring CF mutations models CF disease in-vitro and enabled personalized screens of therapeutic compounds. TMEM16A is a calcium-activated chloride channel that regulates lung basal cell differentiation and modulates CFTR expression. Therefore, leveraging the PSC lung model, the investigators will elucidate the role of TMEM16A in normal and CF epithelial cell development and determine the effects of up-regulating TMEM16A in restoring epithelial function in CF airways by achieving the following deliverables: 1) Generation of the PSC models to study the role of TMEM16A in lung epithelial differentiation in the context of normal and CF airways, 2) Develop a computational model illustrating a functional role of TMEM16A in normal and CF airway epithelia development and, 3) Provide proof-of-concept a CF mutation-independent role of TMEM16A in treating airway CF. This research combines our PSC models with gene-editing and single cell technologies and mathematical modeling to identify an alternative treatment modality for all CF patients and other lung diseases and improve the health, economic and social welfare of Canadians by reducing the burden of healthcare costs.

Lead Investigator:

Michael Garton, Institute of Biomedical Engineering, University of Toronto

Lead Investigator:

John Parkinson,The Hospital for Sick Children

Co-Investigators:

Jason Maynes, The Hospital for Sick Children. William Navarre, Department of Molecular Genetics, University of Toronto.

Lead Investigator:

Agostino Pierro, The Hospital for Sick Children

Co-investigator:

Philip Sherman, The Hospital for Sick Children

Lead Investigator:

Lincoln Stein, Department of Molecular Genetics, University of Toronto