Fáilte chuig an Institiúid um Leigheas Athghiúnach
Welcome to the Regenerative Medicine Institute (REMEDI®)

Prof. Timothy 0'Brien

Phone: 
091-495107
timothy.obrien@nuigalway.ie

Director of REMEDI

Development of gene and cell therapy approaches to vascular disease with a special focus on the augmentation of nitric oxide bioavailability.

Researcher in

Research Project Area: 

Professor O'Brien established the Regenerative Medicine Institute at NUI, Galway (REMEDI).  The focus of the Institute is to exploit the synergies between the technologies of gene delivery and stem cell biology to promote organ regeneration and repair.  The principal initial disease targets of the Institute are ischaemic cardiovascular disease and osteoarthritis.

NO bioavailability

NO bioavailability is diminished in a variety of vascular disease states such as hypertension, hyperlipidemia and diabetic wounds. The PI is interested in a therapeutic approach to these disorders using gene and or cell therapy. The gene therapy approach has focused on targeted expression of nitric oxide isoforms in the diseased vessel site and the use of endothelial progenitor cells as a gene deliver system. The PI also has an interest in the pathogenesis of diabetic vascular disease including the role of endothelial progenitor cel dysfunction.

Positions Held: 

2004-present
Director of the Regenerative Medicine Institute, NUIG and GUH

2001- present
Professor and Head of Medicine, Consultant Endocrinologist
NUIG and Galway University Hospital

1995-2001
Consultant
Division of Endocrinology, Nutrition and Metabolism, Mayo Clinic, Rochester, MN

1999-2001
Associate Professor of Medicine
Mayo Foundation, Rochester, MN

1995-1999
Assistant Professor of Medicine
Mayo Graduate School of Medicine, Rochester, MN

1993-1994
Postdoctoral Fellow
Gladstone Institute of Cardiovascular Disease, San Francisco

1993-1994
Assistant Clinical Professor of Medicine
University of California, San Francisco

1990-1992
Fellow in Endocrinology and Metabolism
Mayo Graduate School of Medicine, Rochester, MN

1988-1990
Resident in Internal Medicine
Medical College of Wisconsin, Milwaukee, WI

1984-1988
Resident in Internal Medicine
Cork Regional Hospital

1996
PhD
National University of Ireland, Cork

1990
MD
National University of Ireland, Cork

1987
MRCP (UK)
Royal College of Physicians, UK

1986
MRCPI Part 2
Royal College of Physicians of Ireland

1986
MRCPI Part 1
Royal College of Physicians of Ireland

Awards & Honours: 

1978
College Scholar; University College Cork
1988
Ainsworth Scholarship; University College Cork
1991-1992
WL Stephenson Fellowship in Clinical Nutrition; Mayo Graduate School of Medicine
1993-1994
Mayo Foundation Scholar; Mayo Graduate School of Medicine
1993
Sprague Award for Excellence in Clinical Medicine; Division of Endocrinology and Metabolism, Mayo Clinic
1997
Outstanding Poster Presentation. Internal Medicine Research Activities Forum, Mayo Clinic
1998
Young Investigator Award. Vascular and Myocardial Aspects of Ischemic Heart Disease. American Heart Association.
1998
Mayo Clinic Internal Medicine Research Award: Adipocyte Macrophage Colony Stimulating Factor (MCSF) Is a mediator of adipose tissue growth.

2005
Stokes Medal, Irish Cardiac Society
2007
Nordisk Lecture, Irish Endocrine Society
2008
48th Graves lecture of the Royal academy of Medicine in Ireland
 

Selected Publications: 

 

Khurana VG, Smith LA, Baker TA, Eguchi D, O’Brien T, Katusic ZS.  Protective vasomotor effects of in vivo recombinant endothelial nitric oxide synthase gene expression in a canine model of cerebral vasospasm.  Stroke 33: 782-789, 2002. Impact Factor  6.499. Cited 36.

 

Zanetti M, Sato J, Katusic ZS, O’Brien T.  Gene transfer of superoxide dismutase isoforms reverses endothelial dysfunction in diabetic rabbit aorta.  Am J Physiol Heart Circ Physiol 280:H2516-H2523, 2001. Impact Factor 3.643. Cited 32.

 

Sato J, Nair KS, Hiddinga J, Eberhardt NE, Fitzpatrick LA, Katusic ZS, O’Brien T. eNOS gene transfer to vascular smooth muscle cells inhibits cell proliferation via upregulation of p27 and p21 and not apoptosis.  Cardiovasc Res 47(4):697-706, 2000. Impact Factor 5.947. Cited 45.

 

Cable DG, Caccitolo JA, Caplice N, O’Brien T, Simari RD, Daly RC, Dearani JA, Mullany CJ, Orszulak TA, Schaff HV.  The role of gene therapy for intimal hyperplasia of bypass grafts.  Circulation 100: II-392-II-396, 1999. Impact Factor 14.595. Cited 34.

 

Onoue H, Tsutsui M, Smith L, Stelter A, O’Brien T, Katusic Z.  Expression and function of recombinant endothelial nitric oxide synthase gene in canine basilar artery after experimental subarachnoid hemorrhage.  Stroke. 28(9):1959-1965, 1998. Impact Factor 6.499. Cited 47.

 

Levine JA, Jensen MD, Eberhardt NL, O'Brien T.  Adipocyte macrophage colony-stimulating factor is a mediator of adipose tissue growth.  J Clin Invest. 101:1557-1564, 1998. Impact Factor 16.559. Cited 64.

 

Kullo IJ, Mozes G, Schwartz RS, Gloviczki P, Tsutsui M, Katusic ZS, O'Brien T.  Enhanced endothelium-dependent relaxations after gene transfer of recombinant endothelial nitric oxide synthase to rabbit carotid arteries.  Hypertension. 30: 314-320, 1997. Impact Factor 7.368. Cited 56.

 

Kullo IJ, Mozes G, Schwartz R, Gloviczki P, Crotty TB, Barber DA, Katusic ZS, O'Brien T.  Adventitial gene transfer of recombinant endothelial nitric oxide synthase to rabbit carotid arteries alters vascular reactivity.  Circulation.  96: 2254-61, 1997. Impact Factor14.595. Cited 61.

 

Chen AFY, Jiang SW, Crotty TB, Tsutsui M, Smith LA, O'Brien T, Katusic ZS. Effects of in vivo adventitial expression of recombinant endothelial nitric oxide synthase gene in cerebral arteries.  Proc Natl Acad Sci USA.  94: 12568-12573, 1997. Impact Factor 9.38. Cited 73.

 

Chen AF, O'Brien T, Tsutsui M, Kinoshita H, Pompili VJ, Crotty TB, Spector DJ, Katusic ZS.  Expression and function of recombinant endothelial nitric oxide synthase gene in the canine basilar artery.  Circulation Research. 80: 327-335, 1997. Impact Factor 9.989. Cited 88.

 

Recent Publications  

 

 Holohan, C, Szegezdi, E, Ritter, T, O’Brien, T, Samali, A. Cytokine-induced Beta-Cell Apoptosis is no-dependent, mitochondria-mediated and inhibited by BCL-XL. J Cell Mol Med. 2008 Apr;12(2):591-606. Epub 2007 Dec 10.

 

Reeve, J, Stenson-Cox, C, O’Doherty, A, Porn-Ares, I, Ares, M, O’Brien, T, Samali, A. OxLDL-induced gene expression patterns in CASMC are mimicked in apoE-/-mice aortas. Biochemical and Biophysical Research Communications 356 (3) 681-6, 2007.

 

Reeve JL, Szegezdi E, Logue SE, Chonaighle TN, O’Brien T, Ritter T, Samali A.  Distinct mechanisms of cardiomyocyte apoptosis induced by doxorubicin and hypoxia converge on mitochondria and are inhibited by Bcl-xL.  J Cell Mol Med. 2007 May-Jun;11(3):509-20.

 

Dwyer RM, Potter-Beirne SM, Harrington KA, Lowery AJ, Hennessy E, Murphy JM, Barry FP, O’Brien T,  Kerin MJ. Monocyte Chemotactic Protein-1 (MCP-1) secreted by primary breast tumors stimulates migration of Mesenchymal Stem Cells (MSCs). Clinical Cancer Research (2007) 13 (17): 5020-5027.

 

Stender S, Murphy M, O’Brien T, Stengaard C, Ulrich-Vinther M, Soballe K, Barry F.  Adeno-associated viral vector transduction of human mesenchymal stem cells.  Eur Cell Mater. 2007 May 31;13:93-9; discussion 99.

 

Rao, VP, Branzoli SE, Miyagi N, O’Brien, T, Tazelaar HD, Russell SJ, McGregor CG. Recombinant adenoviral gene transfer does not affect cardiac allograft vasculopathy.  J Heart Lung Transplant. 2007 Dec:26(12):1281-5.

 

Rooney, G.E., Moran, C., McMahon, S.S., Ritter, T., Maenz, M., Flügel, A., Dockery, P., O’ Brien, T., Howard, L., Windebank, A.J. , Barry, F.P.  Gene-Modified Mesenchymal Stem Cells express functionally active Nerve Growth Factor on an engineered poly lactic glycolic acid (PLGA) substrate.  Tissue Eng Part A. 2008 May;14(5):681-90.

 

Sen S, Conroy S, Hynes SO, McMahon J, O'Doherty A, Bartlett JS, Akhtar Y, Adegbola T, Connolly CE, Sultan S, Barry F, Katusic ZS, O'Brien T.  Gene delivery to the vasculature mediated by low-titre adeno-associated virus serotypes 1 and 5. J Gene Med. 2008 Feb;10(2):143-51

 

Sharif F, Hynes SO, Cooney R, Howard L, McMahon J, Daly K, Crowley J, Barry F, O'Brien, T.  Gene Eluting Stents: Adenoviral-Mediated Delivery of eNOS to the Blood Vessel Wall Accelerates Re-Endothelialization and Inhibits Restenosis. Mol Ther. 2008 Oct;16(10):1674-80. Epub 2008 Aug 19.

 

Mohr A, Lyons M, Deedigan L, Harte T, Shaw G, Howard L, Barry F, O'Brien T, Zwacka R. Mesenchymal Stem Cells expressing TRAIL lead to tumour growth inhibition in an experimental lung cancer model. J Cell Mol Med. 12 (6b); 2628-2643 Dec 2008.

 

Rooney, G.E., Howard, L., O’ Brien, T., Windebank, A. J., Barry, F.P.  Elevation of cAMP Induces Transient Upregulation of Neural Markers in Mesenchymal Stem Cells Cultured in a Defined Element Serum-Free Environment. Stem Cells Dev. 2008 Jun 13.

 

Breen, A., Dockery, P., O’Brien, T., and Pandit, A. Fibrin Scaffold Promotes Adenoviral Gene Transfer and Controlled Vector Delivery.   J Biomed Mater Res A. 2008 May 8.

 

Mylotte LA, Duffy AM, Murphy M, O'Brien T, Samali A, Barry F, Szegezdi E. Metabolic flexibility permits MSC survival in an ischemic environment.  Stem Cells. 2008 May;26(5):1325-36. Epub 2008 Feb 28


Breen, A, Dockery A, O' Brien T. and Pandit A. The use of Therapeutic Gene eNOS delivered via a Fibrin Scaffold Enhances Wound Healing in a Compromised Wound Model. Biomaterials.   2008 Jul;29(21):3143-51. Epub 2008 Apr 28.

 

Gilbert, J. Purcell, J. Strappe, P. McCabe, M. O’Brien, T. O’Dea, S. Comparative evaluation of viral, non-viral and physical methods of gene delivery to normal and transformed lung epithelial cells. Anticancer Drugs. 2008 Sep;19(8):783-8.

 

Molloy AP, Dwyer RM, Martin FT, Griffin TP, Murphy JM, Barry FP, O’Brien T, Kerin MJ. (2008) Mesenchymal Stem Cell (MSC) secretion of chemokines during differentiation  into Osteoblasts, and their potential role in mediating interactions with breast cancer cells.  International Journal of Cancer. 2009 Jan15;124(20:326-32.

 

Breen A, Mc Redmond G, Dockery P, O’Brien T, Pandit A (2008). Assessment of Wound Healing in the Alloxan Induced Diabetic Rabbit Ear Model. J Invest Surg. 2008 Sep-Oct; 21(5): 261-9.

 

Kealy, B, Liew, A, McMahon, JM, Ritter, T, O’Doherty, A, Hoare, M, Greiser, U, Maenz,  M,  O’Shea, C, Barry FP, O’Brien T. Comparison of viral and non-viral vectors for gene transfer to human endothelial progenitor cells. Tissue Eng Part C Methods, 2009 Jun; 15(2): 223-31.

 

MacLoughlin, RJ, Higgins, BD, Laffey JG, O’Brien, T. Optimized Aerosol Delivery to a Mechanically Ventilatd Rodent. Journal of Aerosol Medicine and Pulmonary drug delivery, vol 22, number 3, 2009.

 

Duffy GP, Ahsan T, O’Brien T, Barry FP M. Nerem RM (2008).  Bone Marrow Derived Mesenchymal Stem Cells Promote Angiogenic Processes in a Time and Dose Dependent Manner In vitro.. Tissue Engineering, 2009 Sep; 15(9):2459-70.

 

Rooney, GE, McMahon SS, Ritter T, Garcia Y, Moran C, Madigan NN, Fluegel A, Dockery P, O’Brien T, Howard L, Windebank AJ, Barry F. Neurotrophic Factor-Expressing Mesenchymal Stem Cells Survive Transplantation into the Contused Spinal Cord without Differentiating into Neural Cells. Tissue Eng.2009 Oct:15(10):3049-59.

 

Kulkarni M, Breen A, Greiser U, O’Brien T, Pandit A. Fibrin-Lipoplex System for Controlled Topical Delivery of Multiple Genes. Biomacromolecules 2009 jun 8; 10(6): 1650-4.

Rooney GE, Howard L, O’Brien T, Windebank AJ, Barry FP. Elevation of cAMP n mesenchymal stem cellls transiently upregulates neural markers rather than inducing neural differentiation. Stem Cells Dev. 2009 Apr; 18(3):387-98.

 

O’Loughlin A, Waldron-Lynch F, Cronin KC, Dineen S, Lee J, Griffin D, Casey M, Nusrat N, Jaffrey S, O’Brien T, Dunne F. When a nephrectomy cures hypoglycaemia. BMJ Case reports 2009 (epub ahead of time).

 

Halloday C, Keeney M, Greiser U, Murphy M, O’Brien T, Pandit A. A matrix reservoir for improved control of non-viral gene delivery.  Journal of Controlled Release  2009 Jun 19; 136(3): 220-5.

 

Kulkarni M, Breen A, Greiser U, O’Brien T, Pandit A.  Fibrin-Lipoplex System for Controlled Topical Delivery of Multiple Genes.  Biomacromolecules 2009 June :10(6):1650-4

 

Madsen D, Cantwell ER, O’Brien T, Johnson PA, Mahon BP. AAV-2 induces cell mediated immune responses directed against multiple epitopes of the capsid protein VP1. J Gen Virol. 2009 Nov;90(Pt 11):2622-33

 

McMahon SS, Albermann S, Rooney GE, Moran C, O’Brien T, Hynes J, Garcia Y, Dockery P, Windebank AJ, Barry FB. Effect of Cyclosporin A on functional recovery in the spinal cord following contusion injury.  J Anat 2009 Sept:215(3):267-79.

 

O’Toole D, Hassett P, Contreras M, Higgins DB, McKeown STW, McAuley DF, O’Brien T, Laffey JG. Hypercapnic acidosis attenuates pulmonary epithelial wound repair by an NF-ĸB dependent mechanism.  Thorax. 2009 Nov;64(11):976-82.

 

Eglon M, Duffy AM, O’Brien T, Strappe PM.  Purification of adenoviral vectors by combined anion exchange and get filtration chromatography. J Gene Med. 2009 Nov;11(11):978-89.

 

Madigan NN, O’Brien T, Yaszemski MJ, Windebank AJ.  Current tissue engineering and novel therapeutic approaches to axonal regeneration following spinal cord injury using polymer scaffolds.  Respir Physiol Neurobiol. 2009 Nov 30;169(2):183-99.

 

Kubiak C, De Andres-Trelles F, Kuchinke W, Huemer KH, Thirstrup S, Whitfield K, Libersa C, Barraud B, Grahlert X, Dreier G, Grychtol R, Temesvari Z, Blasko G, Kardos G, O’Brien T, Cooney M, Gaynor S, Schieppati A, Sanz N, Hernandez R, Asker-Hagelberg C, Johansson H, Bourne S, Byrne J, Asghar A, Husson JM, Gluud C, Demotes-Mainard J.  Common definition for categories of clinical reseach: a prerequisite for a survey on regulatory requirements by the European Clinical Research Infrastructures Network (ECRIN). Trials. 2009 Oct 16;10:95.

 

Martin FT, Dwyer RM, Kelly J, Murphy JM, Curran C, Miller N, Hennessy E, Dockery P, Barry FP, O’Brien T, Kerin MJ. Potential Role of Mesenchymal Stem Cells (MSCs) in the Breast Tumor Microenvironment: Stimulation of Epithelial to Mesenchymal Transition (EMT).  Breast Cancer Research and Treatment. 2010 Jan 20.

 

Hoare M, Greiser U, Schu S, Mashayekhi K, Aydogan E, Murphy M, Barry FB, Ritter T, O’Brien T. Enhanced lipoplex-mediatd gene expression in mesenchymal stem cells using reiterated nuclear localization sequence peptides. J. Gene Med. 2010 Feb;12(2):207-18.

 

 

Review Articles 2007-08

1.Liew, A, McDermott, J.H, Barry, F, O’Brien, T. Endothelial progenitor cells for the treatment of diabetic vasculopathy: panacea or pandora’s box? Diabetes Obes Metab. 2007 Sep 6;.

2.Gaffney, MM, Hynes, SO, Barry, F, O’Brien, T. Cardiovascular gene therapy: current status and therapeutic potential. British journal of Pharmacology (2007) 152, 175-188. This article was downloaded (either in pdf or html form) a total of 1,857 times by online subscribers over the 3 months post-publication, the largest number of downloads of all the papers in this issue of BJP.

3.Flynn A, Barry F, O’Brien T. UC-blood derived mesenchymal stromal cells: an overview. Cytotherapy 9(8):7127-726 Oct 2007.

4.McCabe C, O’Brien T. The rational design of beta cell cytoprotective gene transfer strategies: targeting deleterious iNOS expression. Mol Biotechnol 37(1):33-47 Sep 2007.

5. Flynn, A, O’Brien, T. Alferminogene Tadenovac, an angiogenic FGF4 gene therapy for coronary artery disease. IDrugs 2008 11 (4): © The Thomson Corporation ISSN 1369-7056.
 

 

 

Professional and Personal Interests: 

Professional memberships:

  • American College of Physicians
  • American Medical Association
  • American Diabetes Association
  • Royal College of Physicians of Ireland
  • Arteriosclerosis Council of the American Heart Association
  • American Society of Gene Therapy
  • Editorial Board of Endocrine Practice and the Journal of Translational Medicine
  • Editor-in-Chief of Stem Cell Research & Therapy - http://www.stemcellres.com
  • Scientific Editorial Board of Human Gene Therapy
     

 

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