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Characterisation of the role of Panx1/Panx2 in primary endothelial cells

  • Full or part time
  • Application Deadline
    Applications accepted all year round
  • Self-Funded PhD Students Only
    Self-Funded PhD Students Only

Project Description

Pannexins are a family of proteins that are evolutionary related to the gap-junction forming proteins, innexins (1). Three members have been identified, Panx1, Panx2 and Panx3, and they show distinct tissue distribution. Panx1 is the isoform most ubiquitously expressed, and the most widely studied (2). Panx2 is thought to be predominantly expressed in the central nervous system (CNS), whilst Panx3 shows a very limited expression, primarily in the skeleton (3-4). Interestingly, Panx1 has been shown to be implicated in many signalling processes that are important in health and disease (5). There is very little known about Panx2 and Panx3 in terms of function and role in physiology.

Endothelial cells constitute the inner layer of the lymphatic and vascular blood vessels, and dysregulation of these cells is implicated in many cardiovascular diseases such as atherosclerosis (6). Panx1 has been shown to be expressed in endothelial cells and is thought to be involved in mediating vascular inflammation during ischaemia (7-8). The functional expression of Panx2, on the other hand, has not been characterised, although a recent paper reported that it is lowly expressed in lymphatic endothelial cells, but did not investigate its function (9).

We have preliminary RNA-seq data on human arterial and venous endothelial cells isolated from human umbilical cords showing that Panx1 and Panx2 are moderately expressed, however, differentially, in both cell types. Whilst the expression of Panx1 was significantly higher in venous endothelial cells, Panx2 was more prominently expressed in arterial endothelial cells. This is interesting as it raises questions about whether the two isoforms serve different or redundant functions. We aim to investigate the following:

1. Characterisation of Panx1 and Panx2 expression in primary arterial and venous endothelial cells via.

2. Exploration of the potential coupling between Panx1 and Panx2 in primary arterial and venous endothelial cells.

3. Investigation of the functional role of Panx2 in primary arterial and venous endothelial cells.

Funding Notes

No funding is avaialble for this project

References

1. D’Hondt C, Ponsaerts R, De Smedt H, Bultynck G and Himpens B. Pannexins, distant relatives of the connexin family with specific cellular functions? Bioessays. 2009; 31(9): 953-974.
2. Makarenkova H, Shah S and Shestopalov V. The two faces pf pannexins: new roles in inflammation and repair. Journal of Inflammation Research. 2018; 11: 273-288.
3. Le Vasseur M, Lelowski J, Bechberger JF, Sin WC, Naus CC. Pannexin 2 protein expression is not restricted to the CNS. Front Cell Neuroscience. 2014; 8: 392.
4. Iwamoto T, Nakamura T, Doyle A, et al. Pannexin 3 regulates intracellular ATP/cAMP levels and promotes chondrocyte differentiation. Journal of Biological Chemistry. 2010; 285(24): 18948-58.
5. Velasquez S and Eugenin E. Role of Pannxin-1 hemichannels and purinergic receptors in the pathogenesis of human diseases. Frontiers in Physiology. 2014; 5: 1-12.
6. Gimbrone MA and Garcia-Cardena G. Endothelial cell dysfunction and the pathobiology of atherosclerosis. Circulation Research. 2016; 118 (4): 620-636.
7. Good ME, Eucker SA, Bacon HM, et al. Endothelial cell Pannexin1 modulates severity of ischemic stroke by regulating cerebral inflammation and myogenic tone. The Journal of Clinical Investigation Insight. 2018; 3(6): 1-11.
8. Sharma AK, Charles EJ, Zhao Y, et al. Pannexin-1 channels on endothelial cells mediate vascular inflammation during lung ischemia-reperfusion injury. American Journal of Physiology Lung Cellular and Molecular Physiology. 2018; 315(2): L301-L312.
9. Boucher J, Simonneau C, Denet G, et al. Pannexin-1 in Human Lymphatic Endothelial Cells Regulates Lymphangiogenesis. International Journal of Molecular Sciences. 2018; 19(6): 1558.

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