Jessica Plavicki, PhD
Brown University
70 Ship Street
Providence, RI 02903
My lab consists of a team of developmental biologists and environmental scientists working together to understand how genetic mutations and exposure to environmental health contaminants impact brain and heart health. During my undergraduate education and training at the University of Texas at Austin, I developed an appreciation for the importance of utilizing multiple levels of analysis in research to form an integrative understanding of biological processes. As a graduate student in Neuroscience at the University of Wisconsin at Madison, I received training in developmental biology, Drosophila developmental genetics, and biological imaging. My training in developmental biology and a long-standing interest in environmental health science lead me to seek training in toxicology during my next career phase. As a post-doc, I began working with a vertebrate model and extended my training to include zebrafish (Danio rerio) genetics, toxicology, and cardiovascular development. My laboratory at Brown University uses the zebrafish model to study the genetics of brain and cardiovascular development because it provides several distinct advantages. Zebrafish embryos are fertilized externally and develop in an aqueous environment. Passive oxygen diffusion from the environment is sufficient to support embryonic development in the absence of a heartbeat. Consequently, zebrafish embryos with mutations that significantly disrupt cardiovascular development are able to survive and be studied, whereas these mutations would be lethal in a mammalian model. In addition, zebrafish embryos are transparent, which enables us to assess embryonic cardiac function and visualize cardiovascular development in vivo. Despite these critical advantages, the system has yet to be fully exploited to study cardiomyocyte and pharyngeal arch artery development. As a PI, I am committed to increasing diversity in environmental health sciences. I have engaged in outreach activities since early graduate school and will continue to be involved outreach efforts throughout my career. I believe diversity fosters creative, paradigm shifting science.
Congenital 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 80% of congenital heart and vessel defect cases are multifactorial and 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 identify therapeutic targets to treat congenital defects and heart disease by identifying the molecular targets of genes critical for cardiovascular development that are also disrupted by exposure to environmental contaminants. 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, its 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 sox9b 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 and two known mediators of great vessel development, nkx2.5, and stat4. 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 generate critical data that will contribute to our understanding of cardiovascular development and provide putative molecular targets for the development of novel therapeutics to treat congenital heart and vessel defects.
Frank Sellke, MD
Chief of Cardiothoracic Surgery at the Alpert Medical School of Brown University and Rhode Island Hospital
E-mail: fsellke@lifespan.org
https://vivo.brown.edu/display/fsellke
Kristi Wharton, PhD
Professor of Biology Department of Molecular Biology, Cell Biology and Biochemistry
Email: kristi_Wharton@brown.edu
https://vivo.brown.edu/display/kwharton
COMPLETED GRANT SUPPORT
1K99ES023848 (Role: PI)
09/01/2014-08/31/2016
9.0 calendar months
NIH/NIEHS
Ahr2 activation and sox9b function in forebrain and cerebral vascular development
The major goals of this project are to: (1) Test the hypothesis that TCDD exposure disrupts development of the zebrafish brain and cerebral vasculature, (2) Determine in which cell types Ahr2 activation produces brain and cerebral vasculature phenotypes, and (3) Test the hypothesis that downregulation of sox9b mediates the TCDD-induced forebrain and cerebral vascular defects.
CURRENT GRANT SUPPORT
R00ES023848-05 (Role: PI)
02/01/2019-01/31/2020
6.0 calendar months
NIH/NIEHS
Ahr2 activation and sox9b function in forebrain and cerebral vascular development
The major goals of this project are to: (1) Test the hypothesis that TCDD exposure disrupts development of the zebrafish brain and cerebral vasculature, (2) Determine in which cell types Ahr2 activation produces brain and cerebral vasculature phenotypes, and (3) Test the hypothesis that downregulation of sox9b mediates the TCDD-induced forebrain and cerebral vascular defects.
P20GM103652-06 (Role: Project Leader)
07/20/2018-05/31/2020
3.0 calendar months
OSRI COBRE
CPVB COBRE: Project 4: sox9b function in cardiomyocyte and great vessel development
The major goals of this project are to: (1) Identify the downstream targets of sox9b in the zebrafish heart, (2) Determine how loss of sox9b target gene expression disrupts zebrafish great vessel development, and (3) Determine how loss of sox9 target gene expression affects cardiomyocyte and great vessel development in the mouse.
MRI-1919870 (Role: Co-Investigator)
NSF: High resolution mass spectrometer (HRMS) with ultra-high-performance liquid chromatograph (UHPLC)
Ocean State Research Institute
Providence VA Medical Center
Building 35
830 Chalkstone Avenue
Providence RI 02908
T: 401-273-7100
Research Funded by
Research reported in this website was supported by the National Institute of General Medical Science of the National Institutes of Health under grant number P20GM103652.