Project description
Why women are more vulnerable to pulmonary hypertension
Pulmonary hypertension (PH) is a rare, progressive disease marked by activated cells in the pulmonary blood vessels that alter gene expression. Current therapies have minimal survival outcomes. PH mainly affects women, possibly due to sex hormones or incomplete X chromosome inactivation. The ERC-funded FEMALE-PH project aims to investigate the reasons for the female predominance in PH in order to identify new treatments. It will use a rat model for opposite-sex lung transplantation and analyse patient serum for oestrogen metabolites while studying their effects on pulmonary vascular cells. It will also examine incomplete X-chromosome inactivation in PH and explore targeted drug delivery methods to the pulmonary vasculature. Ultimately, it aims to develop new therapies for patients.
Objective
Pulmonary hypertension (PH) is a rare but progressive fatal disease characterized by accumulation of persistently activated cell types in the pulmonary vascular wall exhibiting abnormal expression of genes driving proliferation, inflammation, and metabolism. The currently used vasodilatory therapies have little or no impact on this activated phenotype and therefore offer no cure or even substantial survival benefit. PH has a high female predominance (3:1 to 9:1). This proposal aims to understand the mechanism behind the high female predominance to identify novel therapeutic targets to attenuate disease progression in male and female PH patients.
Female predominance can be linked to sex hormones and/or incomplete X chromosome inactivation (XCI) leading to biallelic expression of immunoinflammatory and metabolic genes. To understand the impact of oestrogen and androgen signalling on abnormal vascular remodelling in PH, I will develop a unique opposite-sex lung transplantation rat model, identify oestrogen metabolites in a large set of patient serum samples and explore their biological relevance using pulmonary vascular cells from male and female PH patients in cell-based assays. Preliminary experiments suggest there is incomplete XCI in PH. I propose to combine sequencing and molecular studies to extensively characterize the impact of incomplete XCI on the physiology of male and female PAH cells and identify genes and druggable targets regulating incomplete XCI in PH. Finally, I will explore a novel pulmonary endothelium-specific drug delivery method to deliver identified promising genes/compounds to selectively inhibit the activated pulmonary vasculature thereby minimalizing side effects compared to current delivery methods.
Together, this high risk-high gain study will dissect the molecular mechanisms underlying the unresolved female predominance in PH and offer novel pulmonary endothelium-specific therapies for both male and female PH patients.
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Project’s keywords as indicated by the project coordinator. Not to be confused with the EuroSciVoc taxonomy (Fields of science)
Programme(s)
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Multi-annual funding programmes that define the EU’s priorities for research and innovation.
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HORIZON.1.1 - European Research Council (ERC)
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HORIZON-ERC - HORIZON ERC Grants
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Call for proposal
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(opens in new window) ERC-2022-STG
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1081 HV Amsterdam
Netherlands
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