权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

sox9b function in cardiomyocyte and great vessel development

sox9b 在心肌细胞和大血管发育中的功能

基本信息

批准号：
9979907
负责人：
Jessica Susan Plavicki
金额：
$ 24.12万
依托单位：
OCEAN STATE RESEARCH INSTITUTE, INC.
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/9979907
关键词：
5&apos Untranslated Regions Address Adult Affect Air Pollution Animal Model Aortic Valve Stenosis Biology Blood Vessels Candidate Disease Gene Cardiac Cardiac Myocytes Cardiac development Cardiopulmonary Cardiovascular system Centers of Research Excellence Cessation of life Clinical Data Code Congenital Abnormality Congenital Heart Defects Data Defect Development Diffusion Dominant-Negative Mutation Ebstein&apos s Anomaly Echocardiography Embryo Endothelial Cells Endothelium Environmental Pollution Etiology Exposure to Gene Expression Genes Genetic Genetic Diseases Genetic Epistasis Genetic Transcription Genetic study Goals Health Heart Heart Atrium Heart Diseases Heart Valves Heart failure Human Immunohistochemistry Incidence Individual Infant Mortality Laboratories Lead Lithium Mammals Mediating Mediator of activation protein Modeling Molecular Molecular Target Morphogenesis Mus Mutation Oxygen Patent Foramen Ovale Patients Pesticides Phenocopy Phenotype Plastics Play Quantitative Reverse Transcriptase PCR Reporting Research Risk Factors Role Tetralogy of Fallot Toxic Environmental Substances Transgenic Organisms United States Vascular Endothelial Cell Ventricular Septal Defects WNT Signaling Pathway Zebrafish campomelic dysplasia cardiogenesis cell type congenital heart disorder epidemiologic data gene function heart function in vivo infant morbidity inhibitor/antagonist innovation knock-down loss of function malformation optogenetics pleiotropism prevent promoter therapeutic target tool transcription factor transcriptome sequencing wasting

项目摘要

PROJECT SUMMARY/ABSTRACT 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.

项目总结/文摘