Congenital abnormalities of the heart and great vessels are the leading cause of infant mortality and morbidity in the United States yet the etiology of most congenital defects remains unknown. Approximately 90% of congenital heart and vessel defect cases are multifactorial. Exposure to environmental contaminants is thought to significantly contribute to the incidence of defects as well adult heart disease. Our long-term goal is to prevent and treat congenital defects and adult heart disease by understanding, in detail, the functions of genes that are critical for cardiovascular development and also disrupted by exposure to environmental toxicants. We have identified a candidate gene, SOX9, that is expressed in multiple cell types in the developing and mature heart and is downregulated in animal models following exposure to environmental toxicants present in air pollution, e-waste, plastics, and pesticides. Human mutations in the SOX9 coding region result in Campomelic Dysplasia (CD), a severe genetic disorder that usually results in death. A number of different congenital heart and great vessel defects have been reported in patients with CD as well as in individuals with mutations affecting SOX9 function. Together, the human loss of function data suggests that SOX9 plays several critical roles in cardiac and great vessel development. However, Sox9b/Sox9 functions in cardiomyocyte and great vessel development have not been investigated using animal models. Our preliminary data indicate that zebrafish Sox9b is essential for cardiomyocyte development and function as well as great vessel formation. Our immediate goal is to identify the molecular mechanisms that mediate the cardiac and great vessel phenotypes observed following loss of Sox9b function in zebrafish and to determine if Sox9b functions are conserved by mammalian Sox9. We are using an innovative multi-species approach and a combination of genetic tools to manipulate zebrafish Soxb and murine Sox9 during cardiovascular development.
In Aim 1. 1, we will determine if Sox9b is an inhibitor of canonical WNT signaling in the developing zebrafish heart.
In Aim 1. 2, we will inhibit Sox9b function in embryonic cardiomyocytes and use RNAseq to identify additional molecular targets of Sox9b during zebrafish heart development.
In Aim 2, we use the cell-type specific manipulations and optogenetics to determine how loss of Sox9b function leads to the great vessel phenotypes and to determine the relationship between Sox9b, Nkx2.5, and Stat4, two known mediators of great vessel development.
In Aim 3, we will extend our understanding of Sox9b function in cardiac development by examining how loss of Sox9 in mouse cardiomyocytes and endothelial cells affects cardiac and great vessel development as well as how loss of Sox9 in the murine heart impacts canonical WNT signaling. Together, these studies will help us understand the endogenous functions of Sox9b/Sox9 and how genetic and/or environmental disruptions in SOX9 function can contribute to congenital heart and great vessel defects in humans.
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