Mots-Clés

Anbalyse de données de snRNAseq

Description

Titre du stage : Landscape of cardiac cellular heterogeneity and response to long-term dioxin exposure

Contexte : The interaction of pollutants with cardiac disease has only recently emerged. 2,3,7,8- tetrachlorodibenzo-p-dioxin (TCDD) is the most toxic and persistent organic pollutant that bioaccumulates in the body through the food chain. The toxicity of TCDD is mediated by the activation of Aryl Hydrocarbon Receptor (AHR), a ligand-activated transcription factor regulating detoxification enzyme expression. In healthy animals, TCDD exposure has been shown to induce mild cardiac hypertrophy. However, it remains unclear what are the cellular and molecular mechanism underlying TCDD cardiotoxicity. The aim of the project is to establish the landscape of cardiac cellular heterogeneity and response to long-term dioxin exposure during the progression of cardiac hypertrophy induced by aging in adult mice.

Objectifs :

- Task 1. Single cell analysis of adult heart upon TCDD exposure. The heart contains many cell types, including cardiomyocytes, vascular cells, fibroblasts and immune cells. Although cardiomyocytes are the primary targets of systemic stress responses, it is becoming clear that non-myocyte cells, especially (cardiac) endothelial cells and their paracrine interactions with cardiomyocytes may be critical in induction of pathological hypertrophy. Using single-nuclei RNA sequencing (snRNA-seq) on hearts exposed to TCDD during aging, we will determine the molecular signature of TCDD on specific cardiac cell types that aggravates heart dysfunction once it is established during aging. This approach will be useful to uncover the specific regulatory circuitries and interactions of each analyzed cardiac cells.

- Task 2. Identification of cardiac stress-responsive cellular lineage. From the single cardiac cell stress Atlas, particular attention will be given to snRNAseq data obtained from cardiomyocyte and endothelial cell populations. More specially, the analysis of the cellular trajectory of each cell’s transcriptome will be helpful to identify the stress-induced cellular dynamic of cardiomyocyte or endothelial cell transcriptomes that may explain the transition from normal to hypertrophic heart. Based on cell-type specific expression of ligands and cognate receptors, we will also analyze the putative intercellular cross-talk between cardiomyocytes and endothelial cells with a special focus on paracrine factors secreted by cardiomyocytes and endothelial cells that may regulate their respective survival, growth, contractile/angiogenic functions, and metabolism under environmental stress.

Travail demandé : Computational single nuclei RNAseq analysis

Compétences techniques recherchées : snRNAseq data analysis : conversion .bcl to fastq ; Demultiplexing ; Quality control ; Filtering and normalization; Clustering analysis; Differential expression ; Interactome. Programming and statistical skills (Python and R). Knowledge and interest in molecular biology and genetics to answer key questions of the research program.