Mending sex differences: Unravelling the female predominance in pulmonary hypertension

Description du projet

Pourquoi les femmes sont-elles plus vulnérables à l’hypertension pulmonaire?

L’hypertension pulmonaire (HTP) est une maladie rare et progressive caractérisée par l’activation de cellules dans les vaisseaux sanguins pulmonaires qui modifient l’expression génétique. Les traitements actuels n’offrent que des perspectives de survie très limitées. L’HTP touche principalement les femmes, peut-être en raison des hormones sexuelles ou d’une inactivation incomplète du chromosome X. Le projet FEMALE-PH, financé par le CER, va se pencher sur les raisons de la prédominance féminine dans l’HTP afin d’identifier de nouveaux traitements. Il s’appuiera sur un modèle de transplantation pulmonaire de sexe opposé chez le rat et analysera le sérum des patients pour y rechercher des métabolites d’œstrogènes tout en étudiant leurs effets sur les cellules vasculaires pulmonaires. Il examinera également l’inactivation incomplète du chromosome X dans l’HTP et explorera les méthodes d’administration ciblée de médicaments dans la vascularisation pulmonaire. À terme, il entend développer de nouvelles thérapies.

Objectif

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.