Henry Cheng, Toronto General Research Institute
Mansoor Husain, Toronto General Research Institute
Jason Fish, Toronto General Research Institute
This proposal addresses two priorities of the Vascular Network: “Development of robust preclinical models of vascular cognitive impairment (VCI)” and “Identifying targets for early detection strategies for populations at high risk for vascular diseases”. Epidemiology has revealed that cardiovascular diseases, such as diabetes, are associated with VCI. While enhanced cerebrovascular inflammation in diabetics likely plays a contributing role in the development of VCI, this is difficult to assess in a non-invasive fashion. Identifying patients at risk for VCI may enable interventions to slow disease progression. Sadly, circulating markers that are specific for VCI are not available. This proposal will utilize a mouse model of type-2 diabetes (T2D), which develops VCI pathology that is similar in many respects to human disease. I will assess circulating microvesicles (MVs) and their microRNA (miR) contents during the course of VCI progression in this model to identify novel markers of the early stages of the disease. I recently obtained intriguing data that demonstrate that circulating MVs are anti-inflammatory in healthy mice, which is mediated in part by the transfer of anti-inflammatory miRs to recipient cells (e.g. endothelial cells and monocytes). I have developed a robust assay to assess the function of MVs that can be utilized to determine whether the anti-inflammatory function of MVs is compromised in mouse models of VCI. Importantly, I have found that MVs isolated from mice with advanced cardiovascular disease lose their anti-inflammatory properties, but the relationship between this observation and development of VCI is not known. This project will combine the expertise of the Husain lab in murine diabetic disease models with the expertise of the Fish lab in the analysis of MVs and miR function. The proposed studies will allow us to explore whether circulating MVs/miRs might be useful functional markers of VCI.