Novel In Vivo Genetic and Single-Cell Genomic Analyses for Understanding Congenital Heart Disease
Abstract
This research project addresses the Fiscal Year 2019 Peer Reviewed Medical Research Program Topic Area Congenital Heart Disease. Congenital heart disease (CHD) is a birth defect that is characterized by improper cardiac development, resulting in the abnormal structure and function of the heart. It is the most common birth defect, affecting approximately 1 percent of the population at varying severities. Some forms of CHD can be so severe that they are lethal at birth. However, other forms of CHD can be more subtle and can go undetected, even into adulthood. Understanding the causes of CHD is critical for military personnel and their families because undiagnosed heart defects can impact health and combat effectiveness. In the military, heart disease in general is a leading cause of death and medical discharge, and CHD is a leading cause of death in military personnel under 35 years of age. Gaining a better understanding of the causes of CHD should lead to improved detection and diagnosis of CHD in military personnel and recruits, ultimately leading to lower death rates and lower costs to the military. Previous studies have determined that genetic mutations to DNA are a significant cause of CHD. These genetic mutations can be inherited from parents, or they can occur spontaneously during a pregnancy. Many studies are now using DNA sequencing, or genome sequencing, of patients with CHD and their families to gain knowledge of the genetic mutations that cause CHD. However, in spite of a large effort in this area, it is estimated that we still only understand about 10 to 20 percent of the genes that, when disrupted by mutations, can cause CHD. If we could gain a better understanding of the genes and DNA mutations that contribute to CHD, then we could potentially make better use of genetic screening of military personnel and recruits to identify individuals that are at risk for CHD. The goal of this research project is to provide an increased understanding of the genetic causes of CHD, leading to more accurate diagnoses of CHD. The scientific hypothesis of this proposal is that we can demonstrate functions for a new set of CHD-candidate genes in heart development by studying these genes in the zebrafish animal model. Over the last 20 years, zebrafish have become a valuable animal model for studying heart defects, and many studies have shown that the genes that are needed for proper heart development in zebrafish also play roles in CHD in humans. Importantly for this proposal, new genetic approaches in zebrafish embryos now allow us to test a large group of genes for their roles in heart development. Our preliminary studies have discovered 128 genes that are outstanding candidates for roles in human heart development and CHD. The rationale for our proposed project is that, if we could confirm the functions of these genes in heart development, then we could significantly impact our understanding of the causes of CHD. This research proposal has two main experimental goals. First, we will use genome engineering approaches in zebrafish embryos to test the roles of the new set of 128 human CHD-candidate genes. Second, we will use advanced molecular profiling technology to gain more precise understanding of how genes involved in CHD can lead to different severities of heart defects. Together, we expect that these studies will significantly advance our understanding of the causes and diagnoses of CHD. This research proposal takes a much-needed innovative approach to discovering new genes that can cause CHD. In fact, through this study, we estimate that we will potentially characterize about 25 percent of the remaining genes involved in CHD. In addition, we will use the currently most powerful strategies and technical approaches available to gain very detailed molecular information on CHD. This project provides a framework for future studies of additional CHD genes as they are identified. We even envision futu
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010433
Entities
People
- Lisa Maves
Organizations
- United States Army