About the Project
Statins, in addition to their ability to lower cholesterol levels, have beneficial effects on the vasculature by preventing the inappropriate release of pro inflammatory factors from endothelial cells. How they do this is not fully understood, however, it is known that statins also inhibit a biochemical pathway that is necessary for the addition of lipid anchors (prenylation) to Rab GTPases preventing them from being inserted into their target membranes. Rab GTPases regulate all aspects of intracellular trafficking including exocytosis and several
Rabs have been shown to play roles in the secretion from endothelial cells. The identification of a Rab GTPase whose lipid modulation mimics statin therapy would provide a specific target for developing novel therapeutics for cardiovascular diseases.
This project will address the effects of statins on endothelial cell secretion by using state of the art Super-resolution microscopy in combination with chemical, molecular and biochemistry technologies.
The questions this project addresses are:
What is the effect of statins on endothelial cell secretion?
How does Rab GTPase prenylation affect secretion?
How does the prenylation of specific Rab GTPases mimic statin therapy?
References
Lynn McKeown
Miteva K, Pedicini L, Beech DJ and McKeown L. Statins mediate anti-inflammatory effects via inhibiting release of P-selectin from Weibel Palade bodies in endothelial cells. Submit to ATVB. Oct 2017.
Wilson LA 1st, McKeown L 1st , Tumova S, Li J, Beech DJ. A long variant of CRACR2A that belongs to the Rab GTPase protein family in endothelial cells. Biochem Biophys Res Commun. 2015 2;456(1):398-402
Rubaiy HN, Ludlow MJ, Henrot M, Gaunt HJ, Miteva K, Cheung SY, Tanahashi Y, Hamzah N, Musialowski KE, Blythe NM, Appleby HL, Bailey MA, McKeown L, Taylor R, Foster R, Waldmann H, Nussbaumer P, Christmann M, Bon RS, Muraki K, Beech DJ. (2017). Picomolar, selective, and subtype-specific smallmolecule inhibition of TRPC1/4/5 channels. J Biol Chem. 292(20):8158-8173.
Li J, Hou B, Tumova S, Muraki K, Bruns A, Ludlow MJ, Sedo A, Hyman AJ, McKeown L, Young RS, Yuldasheva NY, Majeed Y, Wilson LA, Rode B, Bailey MA, Kim HR, Fu Z, Carter DA, Bilton J, Imrie H, Ajuh P, Dear TN, Cubbon RM, Kearney MT, Prasad RK, Evans PC, Ainscough JF, Beech DJ. Piezo1 integration of vascular architecture with physiological force. Nature. 2014 Aug 515, 279-282.
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