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Eoin Brennan

Research Fellow

School Of Medicine
Conway Institute
Belfield
Dublin 4

Tel:
Email: eoin.brennan@ucd.ie

Biography

Dr. Eoin Brennan is a Research Fellow at the Conway Institute, University College Dublin. Eoin graduated from University College Cork in 2004 with an honours degree in Genetics and in 2008 completed his PhD in Prof Peter Maxwell's laboratory at Queen's University Belfast, studying the genetic and epigenetic mechanisms of diabetic kidney disease. Eoin completed part of his PhD studies at Sequenom Inc., San Diego, on a collaborative project investigating DNA methylation in diabetic kidney disease.


In 2009, Eoin moved to UCD to work with Profs. Catherine Godson and Finian Martin to study the genetics and signalling pathways implicated in diabetes and microvascular complications of diabetes. Eoin's research has primarily focused on investigating the pathophysiology of vascular complications of diabetes, including diabetic kidney disease (DKD) and diabetes-associated atherosclerosis (DAA).

In 2014, Eoin commenced a 3-year ELEVATE Marie Curie Fellowship at the Baker IDI Heart and Diabetes Institute, Melbourne, Australia. During this time he worked with Prof.  Mark Cooper to investigate endogenous lipid and micro-RNA therapeutics in complications of Diabetes, with a specific focus on targeting vascular lesions. Current research projects of interest include the use of micro-RNA and pro-resolving lipids as a therapeutic strategy in atherosclerosis and cardiovascular disease.

Professional

             

Employment

Employer: Baker IDI Heart and Diabetes Institute, Melbourne
Position: Research Fellow
Employer: Queen's University Belfast
Position: PhD

Education

Year 2004 Institution: University College Cork
Qualification: BSc Subject: Genetics
         

Publications

     

Peer Reviewed Journals

Brennan E, McEvoy C;Sadlier D;Godson C;Martin F (2014) 'The genetics of diabetic nephropathy'. Genes, 4 (4):596-619. [DOI] [Details]
Wang B, Yao K;Huuskes BM;Shen HH;Zhuang J;Godson C;Brennan EP;Wilkinson-Berka JL;Wise AF;Ricardo SD (2016) 'Mesenchymal Stem Cells Deliver Exogenous MicroRNA-let7c via Exosomes to Attenuate Renal Fibrosis'. Molecular therapy : the journal of the American Society of Gene Therapy, 24 (7):1290-1301. [DOI] [Details]
Brennan EP, Cacace A;Godson C (2017) 'Specialized pro-resolving mediators in renal fibrosis'. Molecular Aspects of Medicine, . [DOI] [Details]
McEvoy C, de Gaetano M;Giffney HE;Bahar B;Cummins EP;Brennan EP;Barry M;Belton O;Godson CG;Murphy EP;Crean D (2017) 'NR4A Receptors Differentially Regulate NF-¿¿B Signaling in Myeloid Cells'. Frontiers in Immunology, 8 . [DOI] [Details]
Brennan E, Wang B;McClelland A;Mohan M;Marai M;Beuscart O;Derouiche S;Gray S;Pickering R;Tikellis C;de Gaetano M;Barry M;Belton O;Ali-Shah ST;Guiry P;Jandeleit-Dahm KA;Cooper ME;Godson C;Kantharidis P (2017) 'Protective Effect of Let-7 miRNA Family in Regulating Inflammation in Diabetes-Associated Atherosclerosis'. Diabetes, . [DOI] [Details]
Brennan, EP,Nolan, KA,Borgeson, E,Gough, OS,McEvoy, CM,Docherty, NG,Higgins, DF,Murphy, M,Sadlier, DM,Ali-Shah, ST,Guiry, PJ,Savage, DA,Maxwell, AP,Martin, F,Godson, C (2013) 'Lipoxins Attenuate Renal Fibrosis by Inducing let-7c and Suppressing TGF beta R1'. Journal of the American Society of Nephrology : JASN, 24 :627-637. [DOI] [Details]
Docherty, N. G., Murphy, M., Martin, F., Brennan, E. P., Godson, C. (2014) 'Targeting cellular drivers and counter-regulators of hyperglycaemia- and transforming growth factor-beta1-associated profibrotic responses in diabetic kidney disease'. Experimental Physiology, 99 (9):1154-62. Available Online [Details]
Todd, JN; Dahlström, EH; Salem, RM; Sandholm, N; Forsblom, C; FinnDiane Study Group; McKnight, AJ; Maxwell, AP; Brennan, E; Sadlier, D; Godson, C; Groop, PH; Hirschhorn, JN; Florez, JC (2015) 'Genetic Evidence for a Causal Role of Obesity in Diabetic Kidney Disease'. Diabetes, 64 (12):4238-4246. [Details]
Shungin, D. et Al. (2015) 'New genetic loci link adipose and insulin biology to body fat distribution'. Nature, 518 (7538):187-196. [DOI] [Details]
Nolan, K.A. and Brennan, E.P. and Scholz, C.C. and Cullen, C. and Ryan, A. and Taylor, C.T. and Godson, C. (2015) 'Paricalcitol protects against TGF-β1-induced fibrotic responses in hypoxia and stabilises HIF-α in renal epithelia'. Experimental Cell Research, 330 (2):371-381. Available Online [DOI] [Details]
Locke, A.E., et al. (2015) 'Genetic studies of body mass index yield new insights for obesity biology'. Nature, 518 (7538):197-206. [DOI] [Details]
Nolan, KA; Brennan, EP; Scholz, CC; Cullen, C; Ryan, A; Taylor, CT; Godson C7. (2014) 'Paricalcitol protects against TGF-β1-induced fibrotic responses in hypoxia and stabilises HIF-α in renal epithelia'. Experimental Cell Research, . [Details]
Kantharidis, P; Hagiwara, S; Brennan, E; McClelland, AD; (2014) 'The study of microRNA in diabetic nephropathy: isolation, quantification and biological function'. JOURNAL OF NEPHROLOGY, . [Details]
Sandholm N, McKnight AJ, Salem RM, Brennan EP, Forsblom C, Harjutsalo V, Mäkinen VP, McKay GJ, Sadlier DM, Williams WW, Martin F, Panduru NM, Tarnow L, Tuomilehto J, Tryggvason K, Zerbini G, Comeau ME, Langefeld CD; FIND Consortium, Godson C, Hirschhorn JN, Maxwell AP, Florez JC, Groop PH; FinnDiane Study Group and the GENIE Consortium (2013) 'Chromosome 2q31.1 associates with ESRD in women with type 1 diabetes'. Journal of the American Society of Nephrology, 24 (10):1537-1543. [Details]
Brennan, E; McEvoy, C; Sadlier, D; Godson, C; Martin, F (2013) 'The genetics of diabetic nephropathy'. Genes, . [Details]
Sandholm, N,Salem, RM,McKnight, AJ,Brennan, EP,Forsblom, C,Isakova, T,McKay, GJ,Williams, WW,Sadlier, DM,Makinen, VP,Swan, EJ,Palmer, C,Boright, AP,Ahlqvist, E,Deshmukh, HA,Keller, BJ,Huang, HT,Ahola, AJ,Fagerholm, E,Gordin, D,Harjutsalo, V,He, B,Heikkila, O,Hietala, K,Kyto, J,Lahermo, P,Lehto, M,Lithovius, R,Osterholm, AM,Parkkonen, M,Pitkaniemi, J,Rosengard-Barlund, M,Saraheimo, M,Sarti, C,Soderlund, J,Soro-Paavonen, A,Syreeni, A,Thorn, LM,Tikkanen, H,Tolonen, N,Tryggvason, K,Tuomilehto, J,Waden, J,Gill, GV,Prior, S,Guiducci, C,Mirel, DB,Taylor, A,Hosseini, SM,Parving, HH,Rossing, P,Tarnow, L,Ladenvall, C,Alhenc-Gelas, F,Lefebvre, P,Rigalleau, V,Roussel, R,Tregouet, DA,Maestroni, A,Maestroni, S,Falhammar, H,Gu, TW,Mollsten, A,Cimponeriu, D,Ioana, M,Mota, M,Mota, E,Serafinceanu, C,Stavar (2012) 'New Susceptibility Loci Associated with Kidney Disease in Type 1 Diabetes'. PLoS Genetics, 8 . [DOI] [Details]
Williams WW, Salem RM, McKnight AJ, Sandholm N, Forsblom C, Taylor A, Guiducci C, McAteer JB, McKay GJ, Isakova T, Brennan EP, Sadlier DM, Palmer C, Söderlund J, Fagerholm E, Harjutsalo V, Lithovius R, Gordin D, Hietala K, Kytö J, Parkkonen M, Rosengård-Bärlund M, Thorn L, Syreeni A, Tolonen N, Saraheimo M, Wadén J, Pitkäniemi J, Sarti C, Tuomilehto J, Tryggvason K, Osterholm AM, He B, Bain S, Martin F, Godson C, Hirschhorn JN, Maxwell AP, Groop PH, Florez JC (2012) 'Association Testing of Previously Reported Variants in a Large Case-Control Meta-Analysis of Diabetic Nephropathy'. Journal of Diabetes, . [DOI] [Details]
Brennan, EP; Morine, MJ; Walsh, DW; Roxburgh, SA; Lindenmeyer, MT; Brazil, DP; Gaora, PO; Roche, HM; Sadlier, DM; Cohen, CD; The GENIE, Consortium; Godson, C; Martin, F; (2012) 'Next-generation sequencing identifies TGF-β1-associated gene expression profiles in renal epithelial cells reiterated in human diabetic nephropathy'. Biochimica Et Biophysica Acta-Molecular Basis of Disease, 1822 (4):5https://rms.u89-599. Available Online [Details]
Brennan, EP; Ehrich, M; O'Donovan, H; Brazil, DP; Crean, JK; Murphy, M; Sadlier, DM; Martin, F; Godson, C; McKnight, AJ; Van den Boom, D; Maxwell, AP; Savage, DA (2010) 'DNA methylation profiling in cell models of diabetic nephropathy'. Epigenetics : official journal of the DNA Methylation Society, 5 (5):396-401. Available Online [Details]
Brennan, EP; Ehrich, M; Brazil, DP; Crean, JK; Murphy, M; Sadlier, DM; Martin, F; Godson, C; McKnight, AJ; Van den Boom, D; Maxwell, AP; Savage, DA (2009) 'Comparative analysis of DNA methylation profiles in peripheral blood leukocytes versus lymphoblastoid cell lines'. Epigenetics : official journal of the DNA Methylation Society, 4 (3):159-164. Available Online [Details]
                                                                                                                                           

Research

Research Interests

The failure of spontaneous resolution underlies chronic inflammatory conditions including the vascular complications of diabetes such as atherosclerosis and kidney disease. Diabetes is associated with complications due in part to chronic elevation of blood glucose levels and hypertension, leading to damage of arteries (cardiovascular disease-CVD) and small blood vessels of the kidney, eye and nervous system. Up to 40% of patients with type 1 and type 2 diabetes will develop diabetic kidney disease (DKD), which remains clinically undetectable until significant kidney damage has developed. CVD accounts for over half of the mortality seen in the diabetic population. Diabetic individuals at risk of DKD and CVD are treated with intensive regimens including strict glycemic control, blood pressure-lowering agents, lipid lowering therapy and antiplatelet agents. However, even under optimal conditions such interventions can offer at best partial protection, and novel therapies are required. My investigations utilize human tissues, animal models, and cell model systems leading to the identification of novel modulators of disease and potential markers of susceptibility and progression of diabetic complications, obesity and vascular diseases. Research projects I currently participate in include:

Project 1: Endogenous lipids as pro-resolution therapeutics in atherosclerosis

The failed resolution of inflammation may be a major contributor to the pathogenesis of CVD, diabetes, and associated complications. The identification of endogenous mediators that promote resolution including lipids and cytokines provide a template for potential mimicry and avoiding the complications associated with chronic anti-inflammatory approaches. Lipoxin A4 [LXA4] is an eicosanoid generated during acute inflammatory responses that promotes the resolution of inflammation. We are interested in exploring the potential of LXA4 and a synthetic analogue, Benzo-LXA4, to modulate vascular complications of diabetes in a murine model (streptozotocin-treated ApoE-/- mice], in human carotid plaque tissue ex vivo and in in vitro models of macrovascular and diabetic kidney disease.

Project 2: miRNA therapeutics in vascular complications of diabetes

microRNAs (miRNAs) are implicated in the development of a wide range of diseases, including atherosclerosis, obesity, and diabetes. Among these miRNAs, aberrant let-7 expression is associated with diseases including liver and lung fibrosis and cancer. In the context of diabetes-associated atherosclerosis, previous reports indicate that circulating let-7 levels are lower in patients with CVD and type 2 diabetes. let-7 levels can be restored to normal levels after therapies frequently used in patients to reduce the risk or progression of CVD, specifically statins or glucose-lowering agents such as metformin (12) or DPP4-inhibitor. We have identified a role for the let-7 miRNA family in renal fibrosis, with let-7 levels reduced in vitro and in experimental models of diabetic and nondiabetic kidney disease.

More recently we discovered that restoration of let-7 expression could provide a new target for an anti-inflammatory approach in diabetic vascular disease. The therapeutic potential of restoring let-7 levels using a let-7 mimic was tested: in vitro in vascular smooth muscle cells using ex vivo in murine aortas, and in vivo via tail vein injection in a 24-h murine model. Furthermore, we delivered let-7 mimic to human carotid plaque ex vivo and observed significant changes to the secretome in response to let-7 therapy. Studies are continuing to further clarify the therapeutic potential of let-7 mimics in vascular diseases.


     

Collaborators

Internal Collaborators

Prof. Catherine Godson, University College Dublin
Prof. Finian Martin, University College Dublin
Dr. John Crean, University College Dublin
Dr. Madeline Murphy, University College Dublin

External Collaborators

Dr. Denise Sadlier, Mater Misericordiae Hospital
Dr. Amy Jayne McKnight, Queen's University Belfast
Prof. Peter Maxwell, Queen's University Belfast
Prof. Barbara Murphy, Mount Sinai, NY
Prof. Joel Hirschhorn, Broad Institute, Boston, MA
Dr. Jose Florez, Massachusetts General Hospital, MA
Prof. Per-Henrik Groop, University of Helsinki, Finland
Dr. Clemens Cohen, University of Zurich, Switzerland
Dr. Matthias Kretzler, University of Michigan, Ann Arbor
Prof Mark Cooper, Bakeri IDI Heart and Diabetes Institute, Melbourne