In response to stress, normal cells possess intrinsic mechanisms allowing their survival and repair. One of these mechanisms is cellular senescence, defined as a permanent cell cycle arrest where the cell remains metabolically active but no longer capable to proliferate. My research program is focusing on the role of cellular senescence in different biological processes including the response to oncogenic and ischemic stress, and also in age-related pathologies such as retinopathy. We recently identified a metabolic pathway, involving oxysterols, regulating the senescence response. We now proposes to investigate the role of the Cholesterol 25-hydroxylase (CH25H) in modulating the entry into cell senescence, and in regulating the secretory phenotype of senescent cells using both cell-based and in vivo approaches. Therefore, we secured funding from the Canadian Institutes of Health Research project grant competition to characterize the molecular functions of cholesterol metabolism in senescence induction and diabetic retinopathy. In addition, we obtained CFI funding to establish a metabolomics core facility at our research center to assess metabolic alterations in senescent cells.
The focus of the research project is to examine the regulation of CH25H and the biological function of 25-hydroxycholesterol in different cellular contexts associated to cellular senescence. The long-term objective will be to provide a better understanding of the role of CH25H in diabetic retinopathy leading to the identification of potential novel therapeutic approaches in the treatment of this disease. To this end, we will integrate several different approaches and systems commonly used in my laboratory to elucidate the crucial roles of CH25H in biological pathways. Using genomic, proteomic, cytological, metabolomic, and genetic approaches, we will investigate the role of cholesterol metabolism on the recruitment establishment of cellular senescence in response to stress and during diabetic retinopathy. Since we observed a critical role of CH25H in mediating pathological vascularization in models of retinopathy, we will investigate the therapeutic potential of targeting oxysterol metabolism in order to treat retinopathy.