Deanery of Biomedical Sciences: In health and disease calcium coordinates changes in gene expression, yet in this context how function and dysfunction are specified is enigmatic. Recent studies have shown that zinc can modulate calcium flux at S/ER resident ion channels in arterial smooth muscles, neurons. The action of zinc can be either protective or destructive. We recently discovered the cell-wide web in pulmonary arterial myocytes and have now extended our studies to neurons. The cell-wide web is a network of cytoplasmic nanocourses demarcated by nanojunctions (<200nm across) formed between sarcoplasmic reticulum (SR) and other organellar membranes, spanning from the plasma membrane to nuclear envelope invaginations (NEIs). This cell-wide web provides discrete lines of communication through which extracellular stimuli direct site-specific calcium flux to coordinate the full panoply of cellular processes. We propose that regulated calcium flux across the outer nuclear membrane into NEI-demarcated cytoplasmic nanocourses contributes to NEI network reconfiguration in support of both cell specification, normal cell function and disease, by providing additional levels of genome regulation that can activate specific gene clusters isolated by NEIs. We propose that zinc modulates calcium flux at NEI resident ion channels (e.g., ryanodine receptors) and thereby triggers gene expression changes, dysfunction and disease. Critically, NEI networks exhibit a high degree of plasticity. We will map whether: (1) Zinc excess and insufficiency reconfigures NEI networks and changes gene expression; (2) Zinc modulates stimulus-specified calcium flux across NEI membranes and thus alters selection NEI segregated genes for expression; (4) Zinc-dependent pathways to NEI remodelling contributes to protective or destructive pathways that impact vascular disease and neuronal apoptosis. To achieve these goals, you will gain expertise in and utilise cell culture, confocal imaging, RNAscope, DNAscope and RNAseq.
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