Muhammad Oneeb Rehman Mian, McGill University

Supervisor: Ernesto Schiffrin, McGill University

T regulatory lymphocytes (Tregs), in part due to the expression of the transcription factor forkhead box P3 (Foxp3), suppress the actions of pro-inflammatory T lymphocytes and reduce inflammation in the vascular wall, and accordingly vascular injury. We intend to investigate the protective role of endogenous Foxp3+ Tregs in aldosterone-induced hypertension, vascular injury, and inflammation by determining whether it is enhanced by conditional Treg depletion in Foxp3DTR (B6.129(Cg)-Foxp3tm3Ayr/J) mice. We hypothesize that subcutaneous injections of diphtheria toxin in Foxp3DTR mice to deplete endogenous Tregs will exaggerate aldosterone-induced hypertension and vascular damage compared to injections of PBS. Eleven-week old male Foxp3DTR mice will be implanted with a dummy pump, or infused with aldosterone for 14 days using Alzet osmotic minipumps while receiving 1% saline to drink. Mice will be treated with diphtheria toxin or PBS at days -2, 2, 5, 8 and 11. Blood pressure will be measured by telemetry, vascular structure and function will be assessed by pressurized myography, and systemic, vascular and kidney inflammation will be assessed by immunofluorescence microscopy and flow cytometry. Our proposed multi-disciplinary research will contribute to the advancement of knowledge by revealing the role of endogenous Tregs in aldosterone-induced hypertension and vascular damage. This will confirm Tregs as a key cellular target for the prevention of hypertension, or to be used as an early biomarker to identify populations at high risk for hypertensive vascular disease. It is hoped that subsequent identification and testing of new drug targets, will result in novel and cost-effective prevention and treatment therapies for hypertension and associated vascular injury in the long run. For these reasons, this research project fits within the Vascular Network aims and priority areas of multidisciplinary, innovate research to identify novel targets or biomarkers, which could be used for prevention and management of hypertension and associated microvascular dysfunction.