Project: “Inflammation and Metabolism in Pulmonary Hypertension are Linked to skewed chromosome X Inactivation: new therapeutic optiONS.”

Acronym	IMPHLeXIONS (Reference Number: JTC-2019_062)
Duration	01/05/2020 - 30/04/2023
Project Topic	Pulmonary arterial hypertension (PAH) is a rare disease of increased blood pressure in lung vessels. It is fatal and affects at least twice as more women as males. Our consortium will follow a novel idea and use state-of-the art technologies to investigate why women are more at risk. Under normal conditions, in every female cell, one of the two X chromosomes is switched off. This inactivation process can, however, be imperfect and lead to the reactivation of silenced copies of genes, including ones that are involved in inflammatory and metabolic processes. Because PAH is associated with increased expression of inflammatory and metabolic genes, we hypothesized that reactivation of the silenced X chromosome genes could be one of the underlying reason for observed sex differences in PAH. We propose to measure X chromosome inactivation in 60 female PAH patients using single-cell RNA sequencing complimented with deep coverage wholeexome sequencing. We will investigate mechanisms behind defective X chromosome silencing, including the role of NANOG and PRDM14 overexpression in the regulation of XISt (a noncoding RNA that coats the inactive X chromosome). Finally, we will test tailored therapeutic approaches to restore proper X-chromosome inactivation and improve PAH.
Network	ERA-CVD
Call	ERA-CVD Joint Transnational Call 2019

Number	Name	Role	Country
1	Quebec Heart and Lung Institute-Université Laval	Coordinator	Canada
2	Ludwig Boltzmann Institute for Lung Vascular Research	Partner	Austria
3	Max-Planck-Institute for Heart and Lung Research	Partner	Germany