Integrity of the cellular transformation barriers in reprogrammed cell
Description: Pluripotent stem cells can differentiate in any cell type and have an unlimited capacity to proliferate. These characteristics make these cells very attractive for studying various cellular functions and differentiation pathways. Thanks to a robust protocol established by Shinya Yamanaka (Nobel prize in 2012) it is now possible to generate induced pluripotent stem cells (iPSC) from any somatic cells. This reprogramming protocol only requires the transient expression of 4 different genes which epigenetically modify cells allowing them to acquire and maintain the state of pluripotence. Although robust and reproducible, this procedure is highly inefficient (typically less than 0.01%) with only few iPSC clones emerging. It was shown that inactivation of the tumor suppressor genes TP53 and Ink4a greatly increases the reprogramming success and it is now believed that transient inactivation of these genes occurs during reprogramming. How these genes are regulated during that process and more importantly whether their numerous functions are maintained in reprogrammed cells is mostly unknown. This information is important because iPSC-derived cells (i.e. neurons and cardiomyocytes) are routinely used for drug discovery and as a tool to study cell biology principles and molecular mechanisms. As such, the goal of our research program is to evaluate the integrity of cellular senescence, apoptosis and DNA repair processes in iPSC-derived cells. Our hypothesis is that cellular reprogramming may lead to abnormal tumor suppressive functions making iPSC-derived cells more prone to cell transformation. More specifically we propose to: 1.Evaluate the ability of iPSC-derived cells to activate the senescence and apoptosis pathways in response to DNA damage and oncogene expression. 2.Evaluate the ability of iPSC-derived cells to proceed to DNA repair (i.e. homologous recombination and none homologous end-joining) in response to a DNA damage. 3.Measure to propensity of iPSC-derived cells to transform following exposure to mutagenic drugs. This research program will reveal whether the integrity of key molecular mechanisms involved in cellular transformation and DNA repair are intact in reprogrammed cells. The long term goals/impacts of this proposal will be improved reprogramming strategies to better preserve genetic integrity and reduce the risks of cellular transformation. The results of this program will be applicable to nearly all laboratories using iPSCs for drug discovery or for studying basic cellular functions/pathways.
Amount: CA$45,000
Funding type: research
Funder scheme: Discovery Grants Program - Individual
Start date: 2023-04-01
End date: 2024-03-31
Investigator: Christian Beauséjour
Institution: Université de Montréal
Funded outputs count: 3
Funder award ID: rgpin-2023-03683
OpenAlex ID: G6073003665