Collaborative Research: The Role of Force, Flow, and Female Sex in Heart Development: Bicuspid Aortic Valve in Turner Syndrome

This research will study how blood flow affects diseases of the heart and blood vessels differently in men and women. The work will lead to new treatments to improve nationwide health. One way to study how diseases affect women and men differently is to include people with Turner Syndrome.

Like men, people with Turner Syndrome have only one X chromosome, but they are born with female features. The goal of this research is to identify X chromosome genes that regulate how heart valve cells respond to forces. This force response affects the development of the bicuspid aortic valve, and can create a birth defect.

This problem is more common in men than in women, but is 50 times more common in people with Turner Syndrome. People with a bicuspid aortic valve and Turner Syndrome often need to have their aortic valves replaced at a relatively young age. Unfortunately, it is very hard to detect bicuspid aortic valve disease, even with imaging.

This research will lead to new treatments for patients who need surgical valve replacement. A broad range of cardiovascular disease patients will benefit from these results, not only those with Turner Syndrome. This project will involve a collaboration between biomedical engineers, geneticists, and cardiologists.

The research team will educate the Turner Syndrome community about bioengineering and the research. By training graduate, undergraduate, and high school students, this project will broaden participation of underrepresented groups in research. It will also advance discovery and understanding while promoting teaching, training, and learning.

X chromosome dosage is a novel regulatory factor for endothelial to mesenchymal transformation. Understanding this novel aspect of cell mechanobiology will be broadly relevant to sexually dimorphic development and disease. This research will address how regulation of endothelial to mesenchymal transformation is involved in bicuspid aortic valve development and fibrocalcific changes of bicuspid valves in adults.

Using cells from Turner Syndrome patients, the research team will quantify a role for X chromosome dosage in mechanical regulation of this transformation by controlling the microenvironment, exogenous mechanical stimuli, and patient-specific characteristics. Finally, inducible transgenic approaches will be used to correct X chromosome gene expression and reverse the transformation defects.

This data will provide transformational new information on the role of X chromosome genes and their mechanobiology in bicuspid aortic valves and identify new therapeutic targets for related diseases that affect millions of patients.

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.