Chong, Nelson - University of Westminster - Department of Life Sciences

个人简介

After graduating from the University of Westminster with a BSc (Hon) Bioscience degree, I studied for a MSc in Pharmacology at Kings College London. My project (supervised by Dr Philip K. Moore) was the first to identify the novel nitric oxide synthase inhibitor L-NOARG and this work was subsequently published in the British Journal of Pharmacology. I then took up a PhD studentship at Kings College London (Physiology) under the supervision of Dr David Sugden, working on the characterisation of the receptors for the pineal hormone melatonin. My postdoctoral post at the Institute of Psychiatry (London), with Drs Clive Coen, Iain C. Campbell and John F. Powell, worked on the initial identification of circadian clock genes in the brain. Thereafter I became a Fogarty Visiting Fellow at the National Institutes of Health (USA), working with Dr David Klein on the first molecular characterisation of the limiting enzyme in melatonin synthesis. I continued to examine the pineal clock system as a Vice Chancellor fellow at the University of Surrey before taking up a Lectureship at the University of Leicester, where I focused on the molecular basis of cardiac function and circadian biology. I have now come full circle and back to my home town London and back to Westminster (2013) where it all began, and this is rather exciting for me. I am very much looking forward to working with my colleagues on many diverse projects including circadian and cardiac biology.

研究领域

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Synchrony between external and internal circadian rhythms and harmony among molecular fluctuations within cells are essential for normal organ biology. Circadian (~24 hrs) clocks exist within multiple components of the cardiovascular system. Molecular circadian clock systems, which are located in almost every cell in the body, are pivotal adaptive intracellular machineries designed to allow the cell, organ, and organism to prepare for an anticipated stimulus prior to its onset such as every day biological processes and demands. These clocks have the potential of affecting multiple cellular processes and, therefore, hold the promise of modulating various aspects of cardiovascular function over the course of the day. Many aspects of cardiovascular physiology are subject to diurnal variations and adverse events such as heart attacks, sudden cardiac death, and arrhythmias, appear to be conditioned by the time of day with highest incident during the morning period. The molecular clockwork is modeled as self-sustained transcriptional and posttranslational interlocking feedback loops, whereby circadian clock genes are periodically suppressed by their protein products with a cycle of ~ 24 hrs. Heterodimeric complexes of basic helix-loop-helix (bHLH) transcription factors CLOCK and BMAL1 (also known as ARNTL) comprise the positive limb of the loop and regulates the expression of Period and Cryptochrome genes via E-box DNA elements (CACGTG). PER and CRY proteins then dimerize and comprise the negative limb of the feedback loop by repressing their own transcription by inhibiting CLOCK:BMAL1. CLOCK:BMAL1 also induce the expression of the nuclear orphan receptor REV-ERBα, which in turn represses Bmal1 transcription, whereas another nuclear receptor (RORα) acts to promote Bmal1 transcription, thereby maintaining a robust circadian cycle. Clock gene mutant/knockout organisms display diverse phenotypes in cardiovascular disease states. Using these animal models, circadian gene arrays have revealed that ~20-60% of all genes/proteins in peripheral tissues are regulated by the circadian clock. For example, adipocyte-specific deletion of Bmal1 results in obesity in mice and Clock mutant mice also display overt phenotype of obesity and metabolic syndrome and RORα mutant mice have severe atherosclerosis. In addition to transcriptional regulatory mechanisms, circadian clocks are involved in regulating chromatin remodeling and epigenetic processes in different tissues and microRNA expression. In addition, genetic association studies have identified SNPs in clock genes that are associated with cardiovascular disease such as type 2-diabetes, coronary artery disease and hypertension. Using a systems approach (molecular, cell, organ and animal models), our focus is to identify and delineate novel gene regulatory networks in cardiac function and define molecular mechanisms that control the expression of these genes critical to human health i.e. how does the clock work, and what (and how) it regulates biological processes in the heart?