Rathnakumar Kumaragurubaran, Toronto General Hospital Research Institute
Supervisor: Jason Fish, Toronto General Hospital Research Institute
A common complication of end-stage renal disease (ESRD) is the accelerated development of cognitive impairment and dementia. The molecular mechanisms responsible are poorly understood. Unfortunately there are no effective treatments for cognitive decline in these patients. In addition, no prognostic tests are available to identify patients that will develop cognitive deficits. Microvascular dysfunction in ESRD patients may contribute to vascular cognitive impairment (VCI). ESRD patients have elevated vascular inflammation and calcification, and cardiovascular (CV) and cerebrovascular pathologies are common in these patients. We will seek to identify functional biomarkers of VCI in ESRD patients by utilizing a large clinical cohort from the Predictors of Arrhythmic and Cardiovascular Risk in ESRD (PACE) study. This is a completed prospective study with a rich repository of self-reported, clinical, CV, cognitive and dialysis-related data as well as a biobank for biomarker assessment in 571 incident dialysis patients (< 6 months on regular outpatient dialysis) recruited in Baltimore and surrounding area, with a comprehensive collection of CV imaging and clinical specimens at baseline (n=400) with repeated measures over 4 years (n=218). This cohort includes primarily younger adults with less confounding of age-related disease and comorbidities.
Recent work from the Fish lab has identified a crucial role for circulating microRNAs (miRs) in regulating vascular inflammation (Appendix 1). We found that healthy endothelial cells secrete extracellular vesicles (EVs) that contain anti-inflammatory miRs that can be transferred to monocytes to suppress their activation. Interestingly, in a diabetic mouse model of VCI we found that circulating EVs have altered miR contents and can induce inflammatory/calcification pathways in recipient endothelial cells. This suggests that EVs and the miRs that they contain may contribute to vascular inflammation/calcification and may therefore be implicated in VCI pathogenesis. We will identify circulating miR and calcification biomarkers associated with microvascular dysfunction, vascular calcification and the development of VCI. We will also determine whether an increase in brain-derived EVs in the blood is indicative of VCI brain pathology. These studies will aid in the early diagnosis and prognosis of disease and these biomarkers may be used to monitor the effectiveness of therapeutic interventions. Our studies will also assess miR function in inflammation and calcification, which may uncover novel therapeutic targets.
Our project will combine the expertise of the Fish lab in vascular inflammation, extracellular vesicle and microRNA biology, the expertise of the Husain lab in cardiovascular pathology, together with the expertise of the Parekh lab in clinical epidemiology and biomarker analysis in ESRD. Our studies will address the devastating impact of VCI in a high-risk population. This unmet clinical need has been identified as a priority area of the Canadian Vascular Network. We are poised to make progress in this research area.