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The Ah receptor is a ligand-activated transcription factor that mediates the induction of the CYP1 family of cytochrome P450s and of several Phase II detoxification enzymes. Induction of these genes is the best characterized AHR function but it does not adequately explain the diversity of AHR-mediated effects, such as its involvement in regulation of growth factor signaling, cell cycle proliferation, differentiation, arrest and apoptosis. My lab has found that disruption of AHR expression levels, or AHR activation by TCDD, results in gene expression changes that perturb cardiomyocyte differentiation in embryonic stem cells, suggesting that during development the AHR coordinates a complex regulatory target network responsible for attainment and maintenance of cardiac homeostasis. The long-term objective of my research is to characterize how specific gene-environment interactions during embryogenesis cause congenital cardiac malformations. Specifically, the central question that we ask is whether interplay during early development between endogenous and toxic/adaptive functions of the aryl hydrocarbon receptor (AHR) and its most potent ligand, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)—a model for many environmental agents—perturbs the concerted differentiation patterns of cardiac cell lineages and leads to congenital cardiac malformations at birth and to adult heart disease later in life. We will determine if down-regulation of Ahr is required to maintain ES cell pluripotency and to assess how TCDD exposure deregulates key signaling pathways during differentiation. The health significance of this work is that in humans and mice, polymorphisms that result in haploinsufficiency in several transcription factor genes affected by TCDD cause congenital cardiac malformations that are also epidemiologically associated with maternal exposure to dioxins and polychlorinated biphenyls during pregnancy and cause human congenital malformations and adult cardiovascular disease. Results from this research will be highly significant to the understanding and prevention of environmental cardiac injury.
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论文共 125 篇作者统计合作学者相似作者
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Eiki Kimura,Maureen Mongan, Bo Xiao, Antonius Christianto,Jingjing Wang,Vinicius S Carreira, Brad Bolon,Xiang Zhang,Katherine A Burns,Jacek Biesiada,Mario Medvedovic,Alvaro Puga,
Disease models & mechanismsno. 3 (2024)
bioRxiv : the preprint server for biology (2023)
crossref(2023)
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