Pulmonary hypertension: sex and notch signalling

Studentship strategic priority area: Basic and Clinical Research
Keywords: Pulmonary hypertension, CADASIL, Nothch signaling

Abstract:
We have recently shown that human pulmonary arterial smooth muscle cells (hPASMCs) and systemic vascular smooth muscle cells (hVSMCs) are regulated differentially by key signalling pathways. For example, estrogenic signalling causes Nox-dependent ROS production in hPASMCs but not in hVSMCs. Recently there has been much interest in the role of the Notch (neurogenic locus notch homologue protein) pathway in both the pulmonary circulation (MacLean's field of research) and small vessel diseases (Touyz's field of research). This project will bring these two groups together to understand the differences in Notch3 signalling in hPASMCs and hVSMCs with a particular focus on pulmonary arterial hypertension (PAH) and CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy).

In this project we will interrogate Notch3 signalling in males and females in vivo animal models of PAH (the Sugen/hypoxic model, the hypoxic model) as well as in transgenic models of CADASIL (mice over-expressing Notch3 with a CADASIL mutation). We will also examine the severity of the disease in both sexes through high fidelity in vivo haemodynamic assessments. We will determine if there are gender differences in the responses of the CADASIL mice to hypoxia-induced PAH.

Lungs and mesenteric beds will be compared for expression of genes and proteins associated with both estrogenic signalling (e.g. estrogen receptors, aromatase, CYP1A1 and CYP1B1, aryl hydrocarbon receptor) and Notch3 signalling (e.g. Notch3, JAG-1,2, secretase, ADAM, NICD etc). We will also study components of the vascular endothelial growth factor (VEGF) pathway (VEGF, VEGFR1-3) as this is down-stream of Notch3 and also involved in the pathobiology of both PAH and CADASIL.

The skills that will be taught for this component include in vivo pulmonary and systemic haemodynamics, cardiac output measurements, animal dosing, surgical skills, molecular biology, western blotting, RT-PCR and genomics.