Lopa Leach

Contact

• workRoom E176a The University of Nottingham Medical School
  Queen's Medical Centre
  Nottingham
  NG7 2UH
  UK
• work0115 82 30175
• fax0115 82 30142
• lopa.leach@nottingham.ac.uk

Biography

please see above.

Teaching Summary

Human Anatomy, Reproductive System and Renal Physiology

Research Summary

Interests

• Vascular dysfunction in Diabetes, specifically pregnancies complicated by diabetes (Type 1, Type 2 and GDM).
• Molecular mechanisms underlying physiological vasculogenesis and angiogenesis.
• Endothelial barrier function.
• Role of VE-cadherin and beta-catenin in pathological angiogenesis.
• Modelling neo-vascularisation in age-related macular degeneration.
• Mathematical modelling of blood flow in the placenta

Techniques

• Ex vivo perfusion of human placental vascular beds.
• In vitro modelling of endothelial angiogenesis.
• In vitro modelling of barrier function.
• Confocal imaging of junctional proteins.
• Tissue culture of primary and immortalised human endothelial, endothelial progenitor and epithelial cells.
• Immunocytochemistry, Immunoblotting, electron microscopy, transfection of cells.

Projects

• In vitro development of a model for age related macula degeneration, (The Wellcome Trust).
• Modelling Flow and Growth in the placenta (Medical Research Council).
• Identification of transcription factors and cognate signal transducing pathways activated during stages of angiogenesis (Association of International Cancer Research).
• Modelling diabetic angiogenesis (Anatomical Society of Great Briatain and Ireland).
• Vascular dysfunction in the human diabetic placenta: molecular mechanisms behind angiogenesis versus permeability changes. (The Anatomical Society of great Britain and Ireland)
• Mathematical modelling of placental flow (Marie Curie, EU)
• VEGF and angiopoietins in vascular permeability
• Local Collaborators

• Professor Oliver Jensen
• Mr A Foss (Ophthalmology) Mr G Bugg (Academic Obstetrics) Professor Penny Gowland (Physics)

UK Collaborators

• Dr Zoe Brooks, University of Sheffield (BHF grant: angiopoietins in sepsis)
• Dr David Bates, University of Bristol (splice variant of VEGF-A in diabetic placenta)

International Collaborators

• Dr Gernot Desoye, University of Graz, Austria.
• Dr K Juuti-Uustilo, University of Tampere, Finland

Recent Publications

• HAMILTON, R.D. AND LEACH, L., 2011. Isolation and properties of an in vitro human outer blood-retinal barrier model. In: NAG, S., ed., The blood-brain and other neural barriers 686. Humana Press. 401-417
• CHERNYAVSKY IL, LEACH L, DRYDEN IL and JENSEN OE, 2011. Transport In The Placenta: Homogenizing Haemodynamics In A Disordered Medium. Philosophical Transactions. Series A, Mathematical, Physical, And Engineering Sciences. 369(1954), 4162-82
• LEACH L, 2011. Placental Vascular Dysfunction In Diabetic Pregnancies: Intimations Of Fetal Cardiovascular Disease? Microcirculation (New York, N.Y. : 1994). 18(4), 263-9
• HAMILTON RD and LEACH L, 2011. Isolation And Properties Of An In Vitro Human Outer Blood-Retinal Barrier Model. Methods In Molecular Biology (Clifton, N.J.). 686, 401-16

• View all publications

Future Research

Endothelial barrier function, junctional adhesion molecules, human placenta, angiogenesis, diabetes mellitus.

Physiological and pathological angiogenesis, adhesion molecules and signalling.

We research into how blood vessels grow (angiogenesis) and maintain a selective barrier (permeability) in health and how it may go wrong in disease. These functions are extremely important in the human placenta, which protects and feeds the growing baby throughout pregnancy. Thus our main study is that into understanding blood vessel function in the human placenta in normal and diabetic pregnancies. The role of the mother's nutrition during pregnancy may also have an effect on the placenta and is a recent inclusion. To aid these studies we also have endothelial cell models in culture (2-D and 3-D) which lets us look at the role of individual key growth factors and into how we may control or revert pathological processes. Our second interest is into diseases of the eye which includes diabetes and age-related macula degeneration. We have a successful human model which mimics the arrangements of the blood vessels in the eye. Again, increased angiogenesis and leakiness can lead to blindness and we are investigating ways to prevent this. Impairment in vascular function, specifically increased angiogenesis and vascular leakage, is a major complication of diseases such as diabetes, cancer and hypertension. The adhesion molecules which hold the lining cells i.e. the endothelial cells together play a role in both these functions. Our group uses ex vivo human perfusion models and in vitro cell cultures to understand the signalling and regulation of these molecules and how they may go wrong, specially in diabetes. Our major interest is the functioning of blood vessels in the human placenta, in normal and diabetic pregnancies. The placenta is vital for fetal nutrition, development, growth and well-being throughout gestation and impaired placental function causes fetal morbidity and mortality. Moreover, in-utero disturbances may lead to fetal programming and increased risk of cardiovascular diseases and diabetes in adulthood. We wish to develop therapeutic strategies to prevent the vascular complications we have shown to exist in the placenta in pregnancies complicated by diabetes. We have a near-physiological, extra-corporeal placental perfusion system which allows us to look at the effect of key factors on trans-placental transport, whilst in vitro models allow more long term effects on angiogenic parameters to be studied. We have a near-physiological, extra-corporeal placental perfusion system which allows us to look at the effect of key factors on trans-placental transport. This system allows monitoring of maternal and fetal blood flow and pressure and lends itself to studies of directional transport. We have expertise into growth of primary endothelial cells in 2-D or 3-D culture systems to study barrier properties and angiogenesis. We have a trilayer model of the outer retinal barrier which allows studies into drug transport as well as hypoxia-mediated neo-vascularisation. Immunocytochemistry, confocal microscopy and real time imaging, as well as standard molecular biology which include immunoblotting are routinely used in our laboratory. We also have expertise of immuno-electron methods and standard transmission electron microscopy. The growth factors of specific interest to us include vascular endothelial growth factor and angiopoietin-1. We have knowledge of the behaviour of junctional adhesion molecules (occludin, VE-cadherin and beta-catenin) in regulating paracellular permeability, endothelial survival and angiogenesis.

• HAMILTON, R.D. AND LEACH, L., 2011. Isolation and properties of an in vitro human outer blood-retinal barrier model. In: NAG, S., ed., The blood-brain and other neural barriers 686. Humana Press. 401-417
• CHERNYAVSKY IL, LEACH L, DRYDEN IL and JENSEN OE, 2011. Transport In The Placenta: Homogenizing Haemodynamics In A Disordered Medium. Philosophical Transactions. Series A, Mathematical, Physical, And Engineering Sciences. 369(1954), 4162-82
• LEACH L, 2011. Placental Vascular Dysfunction In Diabetic Pregnancies: Intimations Of Fetal Cardiovascular Disease? Microcirculation (New York, N.Y. : 1994). 18(4), 263-9
• HAMILTON RD and LEACH L, 2011. Isolation And Properties Of An In Vitro Human Outer Blood-Retinal Barrier Model. Methods In Molecular Biology (Clifton, N.J.). 686, 401-16
• LEACH L and MANN GE, 2011. Consequences Of Fetal Programming For Cardiovascular Disease In Adulthood. Microcirculation (New York, N.Y. : 1994). 18(4), 253-5
• SOUADKIA, NAHED, BROWN, ALAN, LEACH, LOPA and PRITCHARD, DAVID I, 2010. Hookworm (Necator americanus) larval enzymes disrupt human vascular endothelium. The American Journal of Tropical Medicine and Hygiene. 83(3), 549-58
• CHERNYAVSKY, I.L., JENSEN, O.E. and LEACH, L., 2010. A mathematical model of intervillous blood flow in the human placentone Placenta. 31, 44-52
• LEACH, LOPA and MAYHEW, TERRY M, 2009. The intra-uterine environment and placentation. Journal of anatomy. 215(1), 1-2
• LEACH, LOPA, TAYLOR, ALICE and SCIOTA, FLAVIA, 2009. Vascular dysfunction in the diabetic placenta: causes and consequences. Journal of anatomy. 215(1), 69-76
• PLANT, S. D., GRANT, D. M. and LEACH, L., 2007. Surface modification of NiTi alloy and human platelet activation under static and flow conditions Materials Letters. 61(14-15), 2864-2867
• HAMILTON, R.D., FOSS, A.J. and LEACH,L., 2007. Establishment of a human in vitro model of the outer blood-retinal barrier.<b>Journal of Anatomy</b> Blackwell Synergy. Available at: <http://dx.doi.org/10.1111/j.1469-7580.2007.00812.x>
• RUTLAND, C.S., LATUNDE-DADA, A.O., THORPE, A., PLANT, R., LANGLEY-EVANS, S. and LEACH, L., 2007. Effect of gestational nutrition on vascular integrity in the murine placenta Placenta. 28(7), 734-742
• BEBB,J., LEACH,L., ZAITOUN,A., HAND,N., LETLEY,D., THOMAS,R. and ATHERTON,J., 2006. The Effects of Helicobacter pylori on the Cadherin-catenin Complex. Available at: <http://dx.doi.org/10.1136/jcp.2006.036772>
• LEACH, L., BADET, J., BROWNBILL, P., HARRIS, L., KEOGH, R., KALIONIS, B. and WHITLEY, G., 2006. Endothelium, Blood Vessels and Angiogenesis - A Workshop Report Placenta. VOL 27(SUPP/A), S26-S29
• PLANT, S.D., GRANT, D.M. and LEACH, L., 2005. Behaviour of human endothelial cells on surface modified NiTi alloy Biomaterials. 26(26), 5359-5367
• LEACH,L. and MAYHEW,T., 2005. Vasculogenesis and Angiogenesis in the diabetic placenta. In: IVANISEVIC, I, ed., Diabetology of Pregnancy Karger, S. AG, Basel, CHE.
• LEACH,L., 2005. Inter-endothelial junctions and Barrier Integrity.. In: PATTERSON, CAROLYN, ed., Perspectives on Lung Endothelial Barrier Function Elsevier Science BV, Amsterdam.
• LEACH, L., GRAY, C., STATON, S., BABAWALE, M.O., GRUCHY, A., FOSTER, C., MAYHEW, T.M. and JAMES, D.K., 2004. Vascular endothelial cadherin and ß-catenin in human fetoplacental vessels of pregnancies complicated by type 1 diabetes : associations with angiogenesis and perturbed barrier function Diabetologia. 47(4), 695-709
• WILLIS, C.L., LEACH, L., CLARKE, G.J., NOLAN, C.C. and RAY, D.E., 2004. Reversible disruption of tight junction complexes in the rat blood-brain barrier, following transitory focal astrocyte loss. Glia. 48(1), 1-13
• DYE, J, LAWRENCE, L, LINGE, C, LEACH, L, FIRTH, J and CLARK, P, 2004. Distinct patterns of microvascular endothelial cell morphology are determined by extracellular matrix composition. Endothelium. 11(3-4), 151-67
• WRIGHT, T.J., LEACH, L., SHAW, P.E. and JONES, P, 2002. Dynamics of vascular endothelial-cadherin and beta-catenin localization by vascular endothelial growth factor-induced angiogenesis in human umbilical vein cells. Experimental Cell Research. 280(2), 159-168
• LEACH, L., BABAWALE, M.O., ANDERSON, M. and LAMMIMAN, M., 2002. Vasculogenesis, angiogenesis and the molecular organisation of endothelial junctions in the early human placenta. Journal of Vascular Research. 39(3), 246-259
• LEACH, L. and DAVIES, D. C., 2002. The Modulation of Endothelial Cell Permeability: winter meeting of the Anatomical Society of Great Britain and Ireland (ASGBI), London, UK, 2-4 January 2002 Journal of Anatomy. VOL 200(PART 6), 539-540
• LEACH, L., 2002. The phenotype of the human materno-fetal endothelial barrier: molecular occupancy of paracellular junctions dictate permeability and angiogenic plasticity Journal of Anatomy. VOL 200(PART 6), 599-606
• DYE, J F, LEACH, L, CLARK, P and FIRTH, J A, 2001. Cyclic AMP and acidic fibroblast growth factor have opposing effects on tight and adherens junctions in microvascular endothelial cells in vitro. Microvascular Research. 62(2), 94-113
• DYE, J F, JABLENSKA, R, DONNELLY, J L, LAWRENCE, L, LEACH, L, CLARK, P and FIRTH, J A, 2001. Phenotype of the endothelium in the human term placenta. Placenta. 22(1), 32-43
• BABAWALE, M O, LOVAT, S, MAYHEW, T M, LAMMIMAN, M J, JAMES, D K and LEACH, L, 2000. Effects of gestational diabetes on junctional adhesion molecules in human term placental vasculature. Diabetologia. 43(9), 1185-96
• DANTZER, V., LEACH, L. and LEISER, R., 2000. Angiogenesis and Placental Vasculature-A Workshop Report Placenta. VOL 21(SUPP/A), S69-S70
• MAYHEW, T. M., LEACH, L., MCGEE, R., WAN ISMAIL, W., MYKLEBUST, R. and LAMMIMAN, M. J., 1999. Proliferation, Differentiation and Apoptosis in Villous Trophoblast 13-41 Weeks of Gestation (Including Observations on Annulate Lamellae and Nuclear Pore Complexes) Placenta. VOL 20(NUMBER 5/6), 407-422
• LEACH,L., FIRTH,J.A., DYE,J.F. and CLARK,P., 1997. Human placental endothelium expresses an unusual phenotype Journal of Anatomy. 191, 142
• LEACH, L and FIRTH, J A, 1997. Structure and permeability of human placental microvasculature. Microscopy Research and Technique. 38(1-2), 137-44
• LEACH,L., FIRTH,J.A., DYE,J.F. and CLARK,P., 1997. The regulation of cell adhesion molecules in human microvascular endothelial cells by the cAMP pathway Placenta. 18(5-6), A21
• LEACH,L., LAMMIMAN,M.J. and HOBSON,S., 1997. The cadherin-catenin complex in normal and histamine-perfused microvessels of the human term placenta - a confocal study International Journal of Microcirculation Clinical and Experimental. 17(4), 212
• LAMMIMAN,M.J. and LEACH,L., 1997. The cadherin-catenin complex in placental vessels - a confocal analysis Placenta. 18(5-6), A35
• FIRTH, J. A. and LEACH, L., 1997. Structure and Permeability in Human Placental Capillaries - A Review Trophoblast Research. VOL 9/10, 10-205-10-214
• LEACH,L., FIRTH,J.A., DYE,J.F. and CLARK,P., 1997. Human placental microvascular endothelial cells show distinct morphological responses to gels of type 1 collagen and matrigel Journal of Anatomy. 191, 136
• LEACH,L., FIRTH,J.A., DYE,J.F. and CLARK,P., 1997. Distinct morphological responses of endothelial cells to extracellular matrix gels in vitro International Journal of Microcirculation Clinical and Experimental. 17(4), 201-2
• FIRTH, J. A. and LEACH, L., 1996. Not Trophoblast Alone: A review of the Contribution of the Fetal Microvasculature to Transplacental Exchange Placenta. VOL 17(NUMBER 2/3), 89-96
• LEACH, L. and FIRTH, J. A., 1996. Advances in understanding permeability in fetal capillaries of the human placenta: a review of the organization of the endothelial paracellular clefts and their junctional complexes Reproduction, Fertility and Development. VOL 7(NUMBER 6), 1451-1456
• GALUSTIAN, C, DYE, J, LEACH, L, CLARK, P and FIRTH, J A, 1995. Actin cytoskeletal isoforms in human endothelial cells in vitro: alteration with cell passage. In Vitro Cellular and Developmental Biology: Animal. 31(10), 796-802
• LEACH, L, EATON, B M, WESTCOTT, E D and FIRTH, J A, 1995. Effect of histamine on endothelial permeability and structure and adhesion molecules of the paracellular junctions of perfused human placental microvessels. Microvascular Research. 50(3), 323-37
• LEACH, L., BHASIN, Y., CLARK, P. and FIRTH, J., 1994. Isolation of Endothelial Cells from Human Term Placental Villi using Immunomagnetic Beads Placenta. VOL 15(NUMBER 4), 355
• LEACH, L, CLARK, P, LAMPUGNANI, M G, ARROYO, A G, DEJANA, E and FIRTH, J A, 1993. Immunoelectron characterisation of the inter-endothelial junctions of human term placenta. Journal of Cell Science. 104 ( Pt 4), 1073-81
• EATON, B M, LEACH, L and FIRTH, J A, 1993. Permeability of the fetal villous microvasculature in the isolated perfused term human placenta. Journal of Physiology. 463, 141-55
• LEACH, L and FIRTH, J A, 1992. Fine structure of the paracellular junctions of terminal villous capillaries in the perfused human placenta. Cell and Tissue Research. 268(3), 447-52
• LEACH, L, EATON, B M, FIRTH, J A and CONTRACTOR, S F, 1991. Immunocytochemical and labelled tracer approaches to uptake and intracellular routing of immunoglobulin-G (IgG) in the human placenta. Histochemical Journal. 23(10), 444-9
• LEACH, L, EATON, B M, FIRTH, J A and CONTRACTOR, S F, 1990. Uptake and intracellular routing of peroxidase-conjugated immunoglobulin-G by the perfused human placenta. Cell and Tissue Research. 261(2), 383-8
• LEACH, L, EATON, B M, FIRTH, J A and CONTRACTOR, S F, 1989. Immunogold localisation of endogenous immunoglobulin-G in ultrathin frozen sections of the human placenta. Cell and Tissue Research. 257(3), 603-7
• LEACH, L, TRUDGILL, D L and GAHAN, P B, 1987. Immunocytochemical localization of neurosecretory amines and peptides in the free-living nematode, Goodeyus ulmi. Histochemical Journal. 19(9), 471-5
• LEACH, L, LAMMIMAN, M J, BABAWALE, M O, HOBSON, S A, BROMILOU, B, LOVAT, S and SIMMONDS, M J, Molecular organization of tight and adherens junctions in the human placental vascular tree. Placenta.. 21(5-6), 547-57