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Assessing modulation of the cytoskeleton in differing macrophage phenotypes: relevance to macrophage invasion, proteolytic profile and foam-cell formation, during the progression of cardiovascular pathologies

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

About This PhD Project

Project Description

Collectively, cardiovascular pathologies including atherosclerosis, aneurysms and heart failure, account for more deaths world-wide than other disease. Accordingly, a better understanding of the cellular and molecular mechanisms underlying these pathologies is paramount for the identification and development of both biomarkers and treatments of these diseases. The past decade has highlighted the prominent role of macrophages in the development and progression of cardiovascular diseases, however more current research has demonstrated that macrophages can co-exist as varying phenotypes which display an array of differing properties. Recent findings have suggested that macrophage subsets display divergent proteolytic profiles whilst also harbouring differing migratory and invasive capabilities. We have recently identified dynamic alterations in the actin cytoskeleton of macrophage phenotypes that correlate with their protease profile, motility, and morphology. Moreover, the transformation of macrophages into foam-cells exerts dynamic effects on their cytoskeleton, which appears to be dictated in part by their original phenotype. This studentship will test the hypothesis that the actin cytoskeleton is differentially regulated in macrophage subsets and upon foam-cell formation, and subsequently dictates their function and contribution to cardiovascular pathologies such as atherosclerosis.

When applying please select ’Cardiac Surgery PhD’ within the Faculty of Health Sciences.

References

. Hood JD and Cheresh DA. Role of integrins in cell invasion and migration. Nat Rev Cancer. 2002;2:91-100.
2. de Villiers WSJ and Smart EJ. Macrophage scavenger receptors and foam cell formation. J Leukoc Biol. 1999;66:740-746.
3. Libby P, Tabas I, Fredman G and Fisher EA. Inflammation and its Resolution as Determinants of Acute Coronary Syndromes. Circ Res. 2014;114:1867-1879.
4. Sakr SW, Eddy RJ, Barth H, Wang FW, Greenberg S, Maxfield FR and Tabas I. The uptake and degradation of matrix-bound lipoproteins by macrophages require an intact actin cytoskeleton, Rho family GTPases, and myosin ATPase activity. J Biol Chem. 2001;276:37649-37658.
5. Weibel GL, Joshi MR, Jerome WG, Bates SR, Yu KJ, Phillips MC and Rothblat GH. Cytoskeleton disruption in J774 macrophages: Consequences for lipid droplet formation and cholesterol flux. Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids. 2012;1821:464-472.
6. McWhorter FY, Wang T, Nguyen P, Chung T and Liu WF. Modulation of macrophage phenotype by cell shape. Proceedings of the National Academy of Sciences. 2013.
7. Libby P. Inflammation in Atherosclerosis. Arterioscler Thromb Vasc Biol. 2012;32:2045-2051.
8. Johnson JL and Newby AC. Macrophage heterogeneity in atherosclerotic plaques. Curr Opin Lipidol. 2009;20:370-378.
9. Waldo SW, Li Y, Buono C, Zhao B, Billings EM, Chang J and Kruth HS. Heterogeneity of human macrophages in culture and in atherosclerotic plaques. Am J Pathol. 2008;172:1112-1126.
10. Di Gregoli K, Jenkins N, Salter R, White S, Newby AC and Johnson JL. MicroRNA-24 Regulates Macrophage Behavior and Retards Atherosclerosis. Arterioscler Thromb Vasc Biol. 2014;34:1990-2000.
11. Johnson JL, Sala-Newby GB, Ismail Y, Aguilera CNM and Newby AC. Low tissue inhibitor of metalloproteinases 3 and high matrix metalloproteinase 14 levels defines a subpopulation of highly invasive foam-cell macrophages. Arterioscler Thromb Vasc Biol. 2008;28:1647-1653.
12. Johnson JL, Devel L, Czarny B, George SJ, Jackson CL, Rogakos V, Beau F, Yiotakis A, Newby AC and Dive V. A Selective Matrix Metalloproteinase-12 Inhibitor Retards Atherosclerotic Plaque Development in Apolipoprotein E-Knockout Mice. Arterioscler Thromb Vasc Biol. 2011;31:528-535.

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