Computational Methods and Tissue Targeted Gene Therapy Applications in Cardiovascular Disease

Cardiovascular disease is the most common cause of death in the United States, and there are approximately 600,000 new acute myocardial infarction (AMI) cases every year. The long-term impacts of AMI result in increased risk of heart failure and recurrent MI. Identification of molecular targets to reduce the lingering effects of AMI is a major field of research with a wide variety of methods to assess the impact of therapeutic interventions. The work presented in this thesis aims to introduce novel analysis methods for these therapeutics and leverage these to investigate the effects of iNOS expression on post-MI left-ventricular remodeling and function. Aim 1 will focus on the development of 3-dimensional finite element models of the heart for co-registration of a variety of endpoints assessed via cardiac magnetic resonance (CMR) and immunohistochemistry. It will further investigate the usage of tissue clearing methods to investigate thick tissue sections, which can be used to co-register 3D histological models with regional cardiac function. Aim 2 will utilize the computational methods developed in Aim 1 and industry standard CMR endpoints to assess the impact of iNOS knockout in specific cell types on post-MI remodeling and regional function. Cell type specific Cre recombinase expression is combined with a transgenic mouse model featuring a loxP-flanked iNOS allele to produce knockout in both macrophages and cardiomyocytes to investigate the respective contribution of these cell types on iNOS-derived oxidative stress and its influence on post-MI recovery and remodeling.