PHA Proof of Concept Research Grant Winner 2015

Soban Umar, MD, PhD

Soban Umar, MD, PhD

Resident Physician, Molecular Medicine
University of California Los Angeles
Title: “Y Chromosome confers protection against pulmonary arterial hypertension”
Term: December 1, 2015- November 30, 2016

The Jerry Wojciechowski PH Proof of Concept Grant

This Proof of Concept Grant is made possible through a generous donation to PHA from Ms. Betty Lou Wojciechowski in honor of her late husband, Jerry, who lost his battle to PH.

Summary of Research Project:

Pulmonary arterial hypertension (PAH) is characterized by increased pressure in the arteries supplying blood to the lungs leading to overgrowth of right side of the heart, right heart failure and sudden death. The incidence of PAH is higher in female patients indicating that males might have a protective factor that could be exploited as a drug target. The role of sex chromosomes in PAH has not been investigated before. Using two novel mouse models, which allow us to disconnect the complement of sex chromosomes (XX. vs. XY) from the effects of gonadal hormones (testicular vs. ovarian), we discovered that gonadectomized XY mice, irrespective of their gonadal sex, develop less severe PAH than XX mice. Interestingly, the lower susceptibility of XY mice to hypoxic insult was due to the presence of Y chromosome rather than the number of X chromosomes. These results for the first time indicated that the genes encoded on the Y chromosome can protect from PAH. The very small number of Y genes allows us to quickly focus on a small number of candidate genes. Four Y genes expressed consistently in lung/heart (Eif2s3y, Uty, Kdm5d, Ddx3y) are the candidate genes to be investigated here. We aim to find the specific protective Y chromosome gene/genes and study its/their mechanisms of action by knocking it/them down or overexpressing in mice and cells and examining mechanistic role on pulmonary vascular remodeling. Identifying the protective Y chromosome gene(s) would certainly shift the paradigm in the field and will be a stepping-stone toward translational research.