Project 6

Mitigating the effects of accelerated vascular ageing in hypertension

Dysregualted ageing proccess underpin the diseasome of ageing. This includes the development of macro- and microvascular dysfunction. However, therapeutically relevant pathways have yet to be identified. We now seek to gain mechanistic insight into the phenotype of premature vascular ageing in hypertension and cardiovascular disease, and to mitigate its effects using senotherapeutics.

The ESR will study cellular ageing in a range of VSMCs derived from healthy and morbid subjects. They will develop organoid cultures to study physiological ageing in a multicellular environment and in vivo in models of premature ageing and disease. The ESR will evaluate these systems, incorporating cellular growth under morbid conditions, for the ability to mitigate dysregulation of ageing processes by direct use of senotherapeutic agents. In vivo evaluation of the most effective interventions will be undertaken in a pre-clinical model of progeria with associated cardiac and vascular co-morbidities. Planned secondments will be undertaken in the Schurgers and Schalkwijk labs in Maastricht and with partner 3i. The ESR will learn about in vivo visualization of senescent and normatively aged tissue, via state-of-the-art imaging, and receive training in macro- and microvascular phenotyping, both in an experimental and population study context.

Planned secondments: 1. In the Schurgers lab at UM, ESR6 will gain critical insights into isolation, growth and characterisation of VSMCs (3 months). 2. ESR6 will be seconded to Intelligent Imaging to learn about in vivo visualization of senescent and normatively aged tissue via state-of-the-art imaging (1 month). 3. At the Schalkwijk lab at UM, ESR6 will receive training on macro- and microvascular phenotyping (in collaboration with ESR7),