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Deciphering the involvement of circadian clock genes in vascular endothelial dysfunction

Synopsis

Shiftwork and particularly work at night are associated with development of cardiovascular diseases (CVD) such as atherosclerosis and myocardial infarction1. The underlying mechanisms are not well understood. Among other mechanisms it has been postulated that night work leading to circadian disruption may affect vascular endothelial function in development of CVD2,3. The circadian rhythm is maintained by networks of molecular clocks throughout the core and peripheral tissues, including blood vessels and endothelial cells. Circadian clock genes such as CLOCK, BMAL1, CRY1-2 and PER1-3 are critical in maintaining the robust relationship between diurnal variation and the cardiovascular system4. Studying the regulatory role of clock genes in the vascular endothelium may improve our understanding about how night shift work may induce the risk of developing CVD.

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Figure 1: Shiftwork-mediated circadian disruption leading to CVD development

Master project(s) for one or two students

The project aims to elucidate the role of the two clock genes CLOCK and CRY1 in the development of vascular endothelium dysfunction in CVD, by the expression of these in endothelial cells. In this project two human vascular endothelial cell lines (HMEC1 and EA.hy926) will be utilized and the expression of the selected clock genes will be altered by overexpression or depletion using siRNA- or CRISPR-Cas9 technology. The effects on critical endothelial functions will be analyzed. The project will focus on analysis of:

  • Cell senescence and viability (β-galactosidase activity, Alamar Blue and LDH assays)
  • Cell migration (wound-healing assay using Incucyte Zoom)
  • Angiogenesis (endothelial tube formation assay)
  • Permeability (macromolecular tracer assays, and TEER measurement)
  • Inflammation and leukocyte adhesion markers (gene and protein expression by qPCR and Luminex technology)

Supervision

The master project will be a part of the EU Horizon2020 funded ‘Exposome Project for Health and Occupational Research’ (EPHOR) project and will be conducted at the National Institute of Occupational Health (STAMI) in the group of Occupational Toxicology. The master student will join our research group consisting of several researchers, postdocs, PhD and master students, and technicians, ensuring all the help and support needed to perform the suggested experiments. Researcher Johanna Samulin Erdem will act as the main supervisor at STAMI and professor P?l Falnes will be the internal supervisor at the Department of Biosciences, University of Oslo. In addition, postdoctoral researcher Mrinal Kumar Das, and chief scientist and group leader Shan Narui will act as co-supervisors.

References

Puttonen et al., Scand J Work Environ Health 2010, 36(2):96–108

Charles et al., Am J Ind Med. 2016 Nov; 59(11): 1001–1008.

Xu et al., Pharmacological Reviews July 2021, 73 (3) 924-967

Fagiani et al., Signal Transduction and Targeted Therapy, 2022) 7:41

Publisert 16. sep. 2022 10:15 - Sist endret 28. aug. 2024 10:51

Omfang (studiepoeng)

60