Computational and Experimental Investigations of Deformation-Driven Molecular Pathways in Single Right Ventricle Congenital Heart Disease

PROJECT SUMMARY/ABSTRACT
Approximately 1-in-3 children with single right ventricle congenital heart disease develop tricuspid valve
regurgitation within 20 years of Fontan completion. Tricuspid valve regurgitation is associated with a 2.4-times
increased risk of circulatory failure. There are currently no effective medications to treat this regurgitation, so
patients with severe regurgitation undergo additional surgery to restore valve function. Unfortunately, many valve
repairs fail within 5 years and patients develop recurrent tricuspid valve regurgitation. It is currently unknown why
this occurs, but it is possible that cell-driven leaflet growth and remodeling plays an important role. Prior studies
have demonstrated a clear correlation between deformation-driven changes to cellular morphology (specifically
the nuclear aspect ratio) and growth and remodeling of the extracellular matrix. However, our inability to estimate
in-vivo cellular deformations and lack of mechanistic insight connecting cellular deformations to growth and
remodeling endpoints limits our capacity to address tricuspid valve regurgitation for this vulnerable population.
Dr. Laurence is a young investigator with a rich background in computational biomechanics who is uniquely
poised at the Children’s Hospital of Philadelphia to address these shortcomings. Dr. Laurence lacks training in
cellular and molecular biology to define the mechanistic relationship between cellular deformations and tissue
growth and remodeling. The objective of this project is to provide the requisite career development in cellular
and molecular biology so that Dr. Laurence can achieve two specific research goals: (1) define how in-vivo cell
deformations differ for patients with single right ventricle congenital heart disease compared to healthy
biventricular physiology and (2) delineate the mechanisms that translate cellular deformations to tissue growth
and remodeling. Successful completion of these goals will significantly advance the current understanding of
how tricuspid valve regurgitation develops or recurs for children with single right ventricle congenital heart
disease. Furthermore, the proposed career development activities will substantially enrich Dr. Laurence’s
research portfolio and allow him to incorporate realistic biological mechanisms into computational workflows.
This will allow Dr. Laurence to pursue his long-term research goal of improving outcomes for children with single
right ventricle congenital heart disease and competitively pursue independent research funding.