Mending sex differences: Unravelling the female predominance in pulmonary hypertension

Descripción del proyecto

Por qué las mujeres son más vulnerables a la hipertensión pulmonar

La hipertensión pulmonar (HP) es una enfermedad rara y progresiva que se caracteriza por células activadas en los vasos sanguíneos pulmonares que alteran la expresión génica. Los tratamientos actuales tienen unos resultados de supervivencia mínimos. La HP afecta principalmente a las mujeres, posiblemente debido a las hormonas sexuales o a una inactivación incompleta del cromosoma X. El equipo del proyecto FEMALE-PH, financiado por el CEI, pretende investigar las razones del predominio femenino en la HP con el fin de identificar nuevos tratamientos. Se utilizará un modelo murino para trasplante pulmonar de sexo opuesto y se analizará el suero de las pacientes en busca de metabolitos estrogénicos, al tiempo que se estudian sus efectos sobre las células vasculares pulmonares. También se examinará la inactivación incompleta del cromosoma X en la HP y se explorarán métodos de administración de fármacos dirigidos a la vasculatura pulmonar. En última instancia, su objetivo es desarrollar tratamientos nuevos para las pacientes.

Objetivo

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.