This is a project which is currently making use of HPC facilities at Newcastle University. It is active.
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Congenital cardiovascular malformations are a leading cause of morbidity and mortality, with defects such as interrupted aortic arch often arising from abnormal morphogenesis of the fourth pharyngeal arch artery (PAA). This project investigates the genetic and cellular interactions that govern 4th PAA development, focusing on the transcription factors Tbx1 and Pax9, which are implicated in 22q11 deletion syndrome and associated cardiovascular defects. Using single nuclei RNA sequencing (snRNA-seq) data from wild-type and mutant mouse models, the study aims to uncover gene regulatory networks and cell–cell communication pathways critical for arch artery formation. Ultimately, the goal is to identify candidate genes and mechanisms that, when disrupted, lead to congenital heart defects.
Key Aims and Objectives
To define a genetic regulatory network controlling 4th PAA morphogenesis and identify novel candidate genes contributing to congenital cardiovascular malformations.
1. Bioinformatic Analysis of snRNA-seq Data
• Perform UMAP clustering to identify cell populations in pharyngeal arches.
• Detect differentially expressed genes in wild-type vs. Tbx1 and Tbx1;Pax9 mutants.
• Characterize ligand–receptor interactions to map cell–cell communication networks.
2. Validation of Candidate Genes
• Use RNAscope and immunohistochemistry to visualize gene expression in embryos.
• Quantify expression changes in specific cell types (pharyngeal endoderm, neural crest) via qPCR using flow-sorted cells.