Principal Investigator Profile

Professor Tim O'Brien

Biography

Professsor T O’Brien received an honours MB BCh BAO degree from UCC in 1984.  He did internship and general professional training at Cork University Hospital and 1 year as Registrar to Prof DJ O’Sullivan.  He completed a two-year residency in internal medicine at the Medical College of Wisconsin in Milwaukee in 1990 followed by a sub-specialty fellowship in Endocrinology and Metabolism at the Mayo Clinic in Rochester MN in 1992. He was elected to Fellowship of the Royal Colleges of Physicians in Ireland and London in 1986 and 1987, respectively, and to Fellowship of the American College of Physicians in 1995 and the American College of Endocrinology in 1996. He was awarded MD (1993) and PhD (1997) degrees from the National University of Ireland. He is board certified in Internal Medicine and Endocrinology and Metabolism in the USA and is a registered specialist in both specialties in Ireland . 

Upon completion of clinical training in internal medicine and endocrinology in 1990, Professor O'Brien was was awarded a prestigious Mayo Foundation Scholarship.  Under this programme, Prof. O'Brien worked for 2 years at the Gladstone Institute of Cardiovascular Disease at the University of California, San Francisco.

On his return to Mayo Clinic in 1994 he was awarded a Clinician Researcher position. Here Prof. O'Brien established an independent research programme. From 1995-2001 he held positions of Assistant Professor of Medicine at Mayo Graduate School of Medicine,  Assosiate Professor of Medicine at Mayo Foundation and Consultant with the Division of Endocrinology, Nutrition and Metabolism at Mayo Foundation. 

Since his return to Ireland in July of 2001 as Professor and Chairman of Medicine, and Consultant Endocrinologist in Galway University Hospital he established the Regenerative Medicine Institute at NUI Galway with funding in excess of €19 million by Science Foundation Ireland. Since the initial funding of the CSET Prof O’Brien has played a leadership role in many initiatives which have substantially changed the academic profile at NUI Galway and in Ireland.

Webpage:  http://www.remedi.ie/people/prof-timothy-0brien

Research Area:

The focus of the Regenerative Medicine  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.

Current Projects:

Cardiovascular:

The aim of this programme is to develop novel therapeutic approaches for the treatment of atherosclerotic vascular diseases.

The major areas of research are in the use of mesenchymal stem cells and endothelial progenitor cells for cardiac and vascular repair, the development of medical devices for stem cell administration, the use of biomaterials for stem cell delivery in cardiovascular disease and understanding the pathogenesis of diabetic vascular disease.

The cardiovascular work programme has close interactions with the other strands of REMEDI including, stem cell biology, gene therapy, biomaterials science, immunology and advanced stem cell manufacturing.

The applications of this research include:

• Improved medical devices for treatment of occlusive arterial disease
• Understanding host stem cell interaction in the myocardium
• Development of novel systems for stimulating growth of new blood vessels
• Novel therapeutic approaches to enhancing heart tissue viability following damage
• An understanding of the pathogenesis of diabetic vascular disease to identify new therapies

National Stem Cell Manufacturing Facility:

A dedicated facility to produce cellular therapeutic products according to current Good Manufacturing Practice (GMP).

The GMP facility also aims to produce clinical grade viral vectors.

The facility contains a series of separated production suites allowing the parallel manufacture of adenoviral vectors and adult mesenchymal stem cells. The facility has a staff of four production technologists and a laboratory manager.

The facility is also involved in the production of research grade viral vectors to support gene therapy research. Currently, adenoviral, Retroviral and lentiviral vectors are being produced.

List of Key Publications:

Cooney, R, Hynes, SO, Sharif, F, Howard, O’Brien, T. Effect of gene delivery of NOS isoforms on intimal hyperplasia and endothelial regeneration after balloon injury. Gene Therapy(2007) 14, 396-404.

McCabe C, O’Brien T. Beta cell cytoprotection using lentiviral vector-based iNOS-specific shRNA delivery. Biochem Biophys Res Commun. 2007 May 25;357(1):75-80. Epub 2007 Mar 28.

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.

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

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. Journal of Cellular and Molecular Medicine. 2008 Mar-Apr;12(2):591-606. Epub 2007 Dec 10

Breen, A, Dockery, P, O’Brien, T, Pandit, A. Fibrin scaffold promotes adenoviral gene transfer and controlled vector delivery. J Biomed Mater Res A. 2008 May 8.

Breen, A, Dockery, P, O’Brien, T, 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.

Rooney, G, Moran, C, McMahon, S, Ritter, T, Maenz, M, Flugel, A, Dockery,P, O’Brien, T, Howard, L, Windebank, T, Barry, F. 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 Apr 11.

Flynn, A, O’Brien, T. Alferminogene tadenovec, an angiogenic FGF4 gene therapy for coronary artery disease. IDrugs. 2008 Apr;11(4):283-93.

Mylotte, L, Duffy, A, Murphy, M, O’Brien, T, Samali, A, Barry, F, Szegezedi, E. Metabolic flexibility permits mesenchymal stem cell survival in an ischemic environment. Stem Cells. 2008 May;26(5):1325-36. Epub 2008 Feb 28

Review Articles:

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;.

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.

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

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.

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.

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