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Fiona McGillicuddy

Conway Fellow and Wellcome Trust Career Development Fellow

Conway Institute of Biomolecular & Biomedical Research
S056 UCD Conway Institute
University College Dublin
Belfield
Dublin 4

Tel: +353 (0)1 716 6769
Email: fiona.mcgillicuddy@ucd.ie

Biography

I graduated from University College Dublin (UCD) in 2002 with a Bachelor of Science degree in pharmacology. I undertook a PhD in pharmacology under the supervision of Prof. Alan Keenan where I evaluated the potential of novel microparticle systems to act as local drug delivery vehicles for treatment of in-stent restenosis (2002-2006).

After my PhD was completed I moved to the University of Pennsylvania (UPenn) to take up my first postdoctoral fellowship position (2006-2009) under the mentorship of Dr Muredach Reilly and Dr Daniel Rader who have world-renowned expertise in the area of lipid metabolism and in particular high-density lipoprotein (HDL) biology. HDL particles play an essential role in facilitating cholesterol efflux from peripheral cells, including lipid lipid-laden foam cells in atherosclerotic lesions, and deliver this cholesterol back to the liver for elimination in the faeces in a process known as reverse cholesterol transport (RCT). At Upenn my main project was focussed on establishing the impact of lipopolysaccharide (LPS)-evoked inflammation on the efflux capacity of HDL particles (termed HDL function) and also on the subsequent steps of RCT. We demonstrated that inflammation reduces HDL function and markedly impaired movement of cholesterol through the liver to bile and faeces, results which were published in Circulation. These studies highlighted a mechanism by which chronic inflammation may enhance cardiovascular risk.

Chronic inflammation is a classic hallmark of obesity and I developed a specific interest in understanding how inflammation affects adipocyte functionality and insulin resistance. I demonstrated the IFNg markedly impaired adipogenesis via activation of STAT1 in human cell lines, results published in JBC. I decided at this point to take up a second postdoctoral position with Prof. Helen Roche in UCD (2009-2011) where I was the senior investigator on an SFI funded project establishing the role of IL-1 in the development of obesity-induced insulin resistance, results of which were published in diabetes. During this period I gained more expertise in the fields of nutrition and metabolism.

I was awarded a Wellcome Trust Career Development Fellowship in 2012 and conduct my research in the Conway Institute of Biomolecular and Biomedical Research at UCD. The primary focus of research in this fellowship is to establish the mechanisms by which over-nutrition enhances cardiovascular disease risk. A key goal of this research is to establish the effects of the obesigenic environment on the capacity of macrophages to mediate cholesterol efflux to HDL particles. Furthermore the effects of obesity on RCT will be assessed in vivo by monitoring 3H-cholesterol movement from macrophages onto HDL particles and measuring uptake into liver, bile and elimination in the faeces. The obese phenotype will subsequently be manipulated by diet (replacement of saturated fat for monounsaturated fat) or anti-inflammatory regimens to improve metabolic health, but maintain equivalent obesity, and the effects on macrophage-faeces RCT will be monitored. These studies will allow us disentangle effects of diet from effects attributable to the obese phenotype on HDL function and lipid metabolism and will provide greater understanding of the link between diet-obesity and cardiovascular health.

Professional

Honours and Awards

Year: 2012.
Title: Wellcome Trust Research Career Development Award

Associations

Association: American Heart Association, Function/Role: Member
       

Committees

Committee : Quality Review Assessment Committee - School of Public Health
Committee : AREC committee

Employment

Employer: University College Dublin
Position: Wellcome Trust Research Career development fellow
Employer: University College Dublin
Position: Senior Postdoctoral Researcher
Employer: University of Pennsylvania
Position: Postdoctoral Researcher

Education

Year 2006 Institution: University College Dublin
Qualification: PhD Subject: Pharmacology
Year 2002 Institution:
Qualification: BSc Subject:
         

Publications

     

Peer Reviewed Journals

O'Reilly M, Dillon E;Guo W;Finucane O;McMorrow A;Murphy A;Lyons C;Jones D;Ryan M;Gibney M;Gibney E;Brennan L;de la Llera Moya M;Reilly MP;Roche HM;McGillicuddy FC (2016) 'High-Density Lipoprotein Proteomic Composition, and not Efflux Capacity, Reflects Differential Modulation of Reverse Cholesterol Transport by Saturated and Monounsaturated Fat Diets'. Circulation, 133 (19):1838-1850. [DOI] [Details]
Finucane, O.M.a and Lyons, C.L.b and Murphy, A.M.c and Reynolds, C.M.d and Klinger, R.e and Healy, N.P.f and Cooke, A.A.g and Coll, R.C.h and McAllan, L.i and Nilaweera, K.N.j and O'Reilly, M.E.k and Tierney, A.C.l and Morine, M.J.m and Alcala-Diaz, J.F.n and Lopez-Miranda, J.o and O'Connor, D.P.p and O'Neill, L.A.q and McGillicuddy, F.C.r and Roche, H.M.s (2015) 'Monounsaturated fatty acid-enriched high-fat diets impede adipose NLRP3 inflammasome-mediated IL-1β secretion and insulin resistance despite obesity'. Diabetes, 64 (6):2116-2128. Available Online [DOI] [Details]
Finucane OM, Reynolds CM;McGillicuddy FC;Harford KA;Morrison M;Baugh J;Roche HM (2014) 'Macrophage migration inhibitory factor deficiency ameliorates high-fat diet induced insulin resistance in mice with reduced adipose inflammation and hepatic steatosis'. PLoS ONE, 9 (11). [DOI] [Details]
McGillicuddy FC, Reynolds CM, Finucane O, Coleman E, Harford KA, Grant C, Sergi D, Williams LM, Mills KH, Roche HM (2013) 'Long-term exposure to a high-fat diet results in the development of glucose intolerance and insulin resistance in interleukin-1 receptor I-deficient mice'. Physiology, 305 (7):1-44. [DOI] [Details]
Finucane OM, Reynolds CM, McGillicuddy FC, Roche HM (2012) 'Insights into the role of macrophage migration inhibitory factor in obesity and insulin resistance'. Proceedings of the Nutrition Society, 71 (4):622-633. [DOI] [Details]
Oliver, E., McGillicuddy, F. C., Harford, K. A., Reynolds, C. M., Phillips, C. M., Ferguson, J. F., Roche, H. M. (2012) 'Docosahexaenoic acid attenuates macrophage-induced inflammation and improves insulin sensitivity in adipocytes-specific differential effects between LC n-3 PUFA'. J Nutr Biochem, 23 (9):1192-200. Available Online [Details]
de la Llera Moya, M., McGillicuddy, F. C., Hinkle, C. C., Byrne, M., Joshi, M. R., Nguyen, V., Tabita-Martinez, J., Wolfe, M. L., Badellino, K., Pruscino, L., Mehta, N. N., Asztalos, B. F., Reilly, M. P. (2012) 'Inflammation modulates human HDL composition and function in vivo'. Atherosclerosis, 222 (2):390-4. Available Online [Details]
Morine MJ, Toomey S, McGillicuddy FC, Reynolds CM, Power KA, Browne JA, Loscher C, Mills KH, Roche HM (2012) 'Network analysis of adipose tissue gene expression highlights altered metabolic and regulatory transcriptomic activity in high-fat-diet-fed IL-1RI knockout mice'. Nutrition, . [DOI] [Details]
McGillicuddy FC, Roche HM (2012) 'Nutritional status, genetic susceptibility, and insulin resistance--important precedents to atherosclerosis'. Molecular Nutrition and Food Research, 56 (7):1173-1184. [DOI] [Details]
Börgeson E, McGillicuddy FC, Harford KA, Corrigan N, Higgins DF, Maderna P, Roche HM, Godson C (2012) 'Lipoxin A4 attenuates adipose inflammation'. FASEB Journal, 26 (10):4287-4294. [DOI] [Details]
Reynolds CM, McGillicuddy FC, Harford KA, Finucane OM, Mills KH, Roche HM (2012) 'Dietary saturated fatty acids prime the NLRP3 inflammasome via TLR4 in dendritic cells-implications for diet-induced insulin resistance'. Molecular Nutrition and Food Research, 56 (8):1212-1222. [DOI] [Details]
Harford KA, Reynolds CM, McGillicuddy FC, Roche HM (2011) 'Fats, inflammation and insulin resistance: insights to the role of macrophage and T-cell accumulation in adipose tissue'. Proceedings of the Nutrition Society, 70 (4):408-417. [DOI] [Details]
McGillicuddy, F. C., Reilly, M. P., Rader, D. J. (2011) 'Adipose modulation of high-density lipoprotein cholesterol: implications for obesity, high-density lipoprotein metabolism, and cardiovascular disease'. Circulation, 124 (15):1602-5. Available Online [Details]
McGillicuddy FC, Harford KA, Reynolds CM, Oliver E, Claessens M, Mills KH, Roche HM (2011) 'Lack of interleukin-1 receptor I (IL-1RI) protects mice from high-fat diet-induced adipose tissue inflammation coincident with improved glucose homeostasis'. Journal of Diabetes, 60 (6):1688-1698. [DOI] [Details]
Oliver E, McGillicuddy F, Phillips C, Toomey S, Roche HM (2010) 'The role of inflammation and macrophage accumulation in the development of obesity-induced type 2 diabetes mellitus and the possible therapeutic effects of long-chain n-3 PUFA'. Proceedings of the Nutrition Society, 69 (2):232-243. [DOI] [Details]
Zhang, Y., McGillicuddy, F. C., Hinkle, C. C., O'Neill, S., Glick, J. M., Rothblat, G. H., Reilly, M. P. (2010) 'Adipocyte modulation of high-density lipoprotein cholesterol'. Circulation, 121 (11):1347-55. Available Online [Details]
Mehta, N. N., McGillicuddy, F. C., Anderson, P. D., Hinkle, C. C., Shah, R., Pruscino, L., Tabita-Martinez, J., Sellers, K. F., Rickels, M. R., Reilly, M. P. (2010) 'Experimental endotoxemia induces adipose inflammation and insulin resistance in humans'. Diabetes, 59 (1):172-81. Available Online [Details]
McGillicuddy, F. C., Chiquoine, E. H., Hinkle, C. C., Kim, R. J., Shah, R., Roche, H. M., Smyth, E. M., Reilly, M. P. (2009) 'Interferon gamma attenuates insulin signaling, lipid storage, and differentiation in human adipocytes via activation of the JAK/STAT pathway'. J Biol Chem, 284 (46):31936-44. Available Online [Details]
Shah, R., Lu, Y., Hinkle, C. C., McGillicuddy, F. C., Kim, R., Hannenhalli, S., Cappola, T. P., Heffron, S., Wang, X., Mehta, N. N., Putt, M., Reilly, M. P. (2009) 'Gene profiling of human adipose tissue during evoked inflammation in vivo'. Diabetes, 58 (10):2211-9. Available Online [Details]
McGillicuddy, F. C., de la Llera Moya, M., Hinkle, C. C., Joshi, M. R., Chiquoine, E. H., Billheimer, J. T., Rothblat, G. H., Reilly, M. P. (2009) 'Inflammation impairs reverse cholesterol transport in vivo'. Circulation, 119 (8):1135-45. Available Online [Details]
McGillicuddy, F. C., Lynch, I., Rochev, Y. A., Burke, M., Dawson, K. A., Gallagher, W. M., Keenan, A. K. (2006) 'Novel plum pudding gels as potential drug-eluting stent coatings: controlled release of fluvastatin'. J Biomed Mater Res A, 79 (4):923-33. Available Online [Details]
McGillicuddy, F. C., O'Toole, D., Hickey, J. A., Gallagher, W. M., Dawson, K. A., Keenan, A. K. (2006) 'TGF-beta1-induced thrombospondin-1 expression through the p38 MAPK pathway is abolished by fluvastatin in human coronary artery smooth muscle cells'. Vascul Pharmacol, 44 (6):469-75. Available Online [Details]
McGillicuddy, F.C.>, Lynch, I., Rochev, Y.A., Burke, M., Dawson, K.A., Gallagher, W.M. Keenan, A.K.; (2006) 'Novel plum pudding gels as potential drug-eluting stent coatings: Controlled release of fluvastatin'. JOURNAL OF BIOMEDICAL MATERIALS RESEARCH, . [Details]
McGillicuddy F, Lynch I, Dawson KA, Keenan AK.; (2004) 'Evaluation of novel 'plum pudding' gels as vehicles for local delivery of fluvastatin'. American Journal of Cardiology, 94 (Suppl1):224E-224E. [Details]
Wilson, SJ; Gorelov, AV; Rochev, YA; McGillicuddy, F; Dawson, KA; Gallagher, WM; Keenan, AK; ; (2003) 'Extended delivery of the antimitotic agent colchicine from thermoresponsive N-isopropylacrylamide-based copolymer films to human vascular smooth muscle cells'. Journal of Biomedical Materials Research - Part A, 67A (2):667-673. [Details]
 

Conference Publications

Oliver, E,McGillicuddy, F,Phillips, C,Toomey, S,Roche, HM (2010) PROCEEDINGS OF THE NUTRITION SOCIETY Postgraduate Symposium The role of inflammation and macrophage accumulation in the development of obesity-induced type 2 diabetes mellitus and the possible therapeutic effects of long-chain n-3 PUFA , pp.232-243 [DOI] [Details]
Oliver E, McGillicuddy F, Philips C, Toomey S, Roche HM (2010) ; (2010) The role of inflammation and macrophage accumulation in the development of obesity induced type 2 diabetes mellitus and the possible therapeutic effects of LC n-3 PUFA Nutrition Society Conference [Details]
                       

Abstract

McGillicuddy, F,Lynch, I,Dawson, KA,Keenan, AK (2004) Evaluation of novel plum-pudding gels as vehicles for local delivery of fluvastatin. Abstract [Details]
                                                               

Research

Research Interests

My research interests are to understand the link between diet - obesity - inflammation and cardiovascular disease. More specifically I'm interested at manipulating the obese phenotype with either diet (replacing saturated fats with less inflammatory monounsaturated fats) or supplementing high-fat diets with anti-inflammatory agents and determining the consequences for metabolic health and cholesterol metabolism. 
 
My studies focus on evaluating the effects of obesity and diet on the efflux capacity of high-density lipoprotein (HDL) particles ex vivo. We also use an in vivo model to track reverse cholesterol transport. In these studies J774 macrophages labeled with 3H-cholesterol are injected in vivo and movement of 3H-cholesterol from macrophages onto HDL particles and uptake of cholesterol into liver, bile and faeces is tracked. I have previously shown that inflammation markedly impairs this process and I hypothesize that high-fat diet induced inflammation will similarly impair reverse cholesterol transport.

I am also interested in the consequences of inflammation on the cellular efflux capacity of macrophages and in particular am interested in the consequences for ABCA1-dependent efflux.  Ongoing research is establishing the effects of M1 and M2 macrophage polarization on cholesterol efflux potential of macrophages.

From a translational perspective I am interested in evaluating HDL function in human cohorts (lean, healthy obese and unhealthy (inflamed) obese individuals). These studies are ongoing and I am working closely with the Institute for Food and Health and Prof. Donal O'Shea's group at St. Vincent's Hospital to carry out these studies.

Research Projects

Sponsor : University College Dublin (UCD)
Title : School funded research account
Start Date / End Date : 01-DEC-14 / 30-JUN-19
Sponsor : University College Dublin (UCD)
Title : Investigating high-density lipoprotein (HDL) particle function and composition in metabolically healthy and unhealthy obesity.
Start Date / End Date : 01-APR-15 / 30-SEP-16
Sponsor : The Wellcome Trust (WT)
Title : Functional consequences of obesity-induced adipose tissue inflammation on high-density lipoprotein (HDL) acceptor capacity and reverse cholesterol transport (RCT)
Start Date / End Date : 01-MAR-12 / 31-OCT-17
   

Collaborators

Internal Collaborators

I work very closely Professor Helen Roche in the Conway Institute. Both of our groups have a particular interest in obesity-associated inflammation and establishing novel mechanisms to modulate this inflammation.
 
I am also associated with the Institute for Food and Health and am working closely with the researchers involved in the MECHE study. This study is looking at metabolic health in a cohort of over 200 individuals and I am currently measuring HDL function in this cohort.

I am also collaborating with Prof Donal O'Shea and Prof. Carel le Roux on the clinical side and hope to evaluate HDL function in more diseased obese cohorts in the future. 

External Collaborators

I closely collaborate with my previous mentors at the University of Pennsylvania (UPenn) including Prof. Muredach Reilly,  Prof. Daniel Rader,  Prof. George Rothblat, Dr. Margarita de la Lera Moya and Dr. Jeffrey Billheimer. This group of collaborators established many of the models that I am currently using in my research including the HDL function assays and the  in vivo macrophage- faeces reverse cholesterol transport model. I visit this laboratory on an annual basis to maintain these strong collaborations.