Regulation of Cardiogenesis by GATA Transcription Factors
Abstract
This project relates directly to the Topic Area of Congenital Heart Disease because it precisely targets the area of encouragement identified as “Research to improve the understanding of the causes of congenital heart defects.” Congenital heart disease refers to a group of disorders that arise from problems with the structure and function of the heart at birth. These represent the largest class of birth defects, including up to 1% of newborns, and therefore are a major source of illness to our military personnel and their families. Forming a heart requires taking a fairly simple tube and fashioning it into a highly ordered four chambered organ; this is a tremendously complex “plumbing” project and a variety of things can go wrong, leading to structural abnormalities that affect the ability of the heart to pump blood efficiently. Sometimes these can be very serious defects that are either incompatible with life (responsible for up to 10% of stillbirths) or need to be surgically repaired upon birth. However, the defects can also be much more subtle and only noticed over time as heart function declines, even into adulthood. Regardless, the root cause is thought to be from abnormal formation of the heart, with a major genetic component that may also be influenced by the environment. It may even be caused by having too few or dysfunctional heart cells. Many of the key genes that control heart formation have been discovered in animal model systems, and these include regulatory proteins (transcription factors) that bind to DNA and turn genes on and off. Among these are genes that encode three highly related proteins called Gata4, Gata5, and Gata6 (referred together as Gata456). Remarkably, human genetic studies have since shown that mutations in these Gata456 genes are associated with human congenital heart disease. Humans have two copies of each gene, one inherited from the mother and one from the father. Complete loss of both copies of any one Gata456 gene might cause embryonic death, and the human mutations are typically found on only one chromosome. The mutations are probably not sufficient to cause heart disease, since family members with the same mutations can have serious, moderate, or even no apparent disease. The mutations associate with disease, and we know from animal models that the genes are very important for heart development, but the actual reason why Gata456 mutations cause disease is not known. This needs to be discovered to develop cellular or drug therapies to cure disease, or block disease from occurring in patients who carry mutant genes and are at risk of developing heart disease. We hypothesize that we can understand the cause of at least some congenital heart disease by identifying the critical genes controlled by Gata456 that fail to be regulated normally when Gata456 genes are mutated. We created a “toolkit” to test this hypothesis comprised of zebrafish that carry mutations in each gene, so that we can study how this affects heart development and to identify all the genes that are improperly regulated in the mutant embryos and growing fish. While the zebrafish model provides great advantages to study organ development, we also need to interpret the results in the context of human biology. For this purpose, our toolkit also includes human embryonic stem cell lines with defined mutations in each gene, which we can use to generate cardiac cells in vitro “in a petri dish” and compare the relative changes in gene expression and heart cell function. Finally, we also made stem cells from patients with congenital heart disease who have specific Gata456 mutations. These will help us to identify additional genes that cooperate with Gata456 mutations to cause disease. Our project is designed to comprehensively identify genetic and cellular programs that go wrong during heart development when Gata456 genes are mutated. We believe it is likely that the same pathways are defective in patie
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1710661
Entities
People
- Todd Evans
Organizations
- United States Army
- Weill Cornell Medicine