Mending sex differences: Unravelling the female predominance in pulmonary hypertension

Descrizione del progetto

Perché le donne sono più vulnerabili all’ipertensione polmonare

L’ipertensione polmonare (IP) è una malattia rara e progressiva caratterizzata da cellule attivate nei vasi sanguigni polmonari che alterano l’espressione genica. Le terapie attuali hanno risultati minimi in termini di sopravvivenza. L’IP colpisce soprattutto le donne, forse a causa degli ormoni sessuali o dell’inattivazione incompleta del cromosoma X. Il progetto FEMALE-PH, finanziato dal CER, mira a indagare le ragioni della predominanza femminile nella IP, al fine di identificare nuovi trattamenti. Utilizzerà un modello di ratto per il trapianto polmonare da sesso opposto e analizzerà i metaboliti degli estrogeni nel siero dei pazienti, studiandone al contempo gli effetti sulle cellule vascolari polmonari. Verrà inoltre esaminata l’inattivazione incompleta del cromosoma X nell’IP e verranno esplorati i metodi di somministrazione mirata di farmaci alla vascolarizzazione polmonare. In definitiva, l’obiettivo è quello di sviluppare nuove terapie per i pazienti.

Obiettivo

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.