Stephen Matthews

Degrees: Ph.D 1992 (Cambridge)

Courses Taught :  PSL1080, PSL498, PSL421, SCS2159

Research Synopsis

Keywords: Developmental neuroendocrinology, Hypothalamic-pituitary-adrenal (HPA) axis, Fetus, Programming, Behaviour, Endocrinology, Gene-environment interactions, Epigenetics, Drug transport, Multidrug resistance, Placenta, Blood-brain barrier, Hippocampus.

Detailed Description:
Programming of Neuroendocrine Function and Behaviour
A major research focus is to understand the mechanisms of hypothalamo-pituitary-adrenocortical (HPA) development, and how these mechanisms can be modified or programmed by fetal environment. This is important because a number of adult pathologies, including diabetes, hypertension and depression, have been associated with chronic changes in HPA function. This area has become known as the Developmental Origins of Health and Disease (DOHaD). We are particularly interested in establishing the effects of fetal exposure to glucocorticoids and maternal nutrient restriction on development of neuroendocrine function and behaviour. These studies are clinically relevant because pregnant women, at risk of delivering prematurely are treated with glucocorticoids to mature the fetal lungs. With respect to nutrient restriction, it is common for women particularly in the developing world to be undernourished during pregnancy. The effects of these perturbations on brain and neuroendocrine development are poorly understood. Most recently, we have discovered that prenatal glucocorticoid exposure and maternal undernutrition during pregnancy can lead to transgenerational influences on HPA function, cardiovascular function and behaviour. We are now investigating the mechanisms involved in this process of fetal programming. Emerging evidence from the laboratory suggests that these include altered maternal adaptation to pregnancy and epigenetic modification. Epigenetic modification or marking of the genome may represent a critical mechanism by which the environment ‘talks’ to the genome, leading to life-long alterations in susceptibility to disease. We are now beginning to translate our findings to the human. By understanding the mechanisms involved in life-long programming, we will be in a position to develop interventions focused towards preventing development of certain chronic diseases.

Role of Drug Resistance Proteins in Pregnancy: Fetal Protection
A group of drug transporters in the ATP binding cassette (ABC) superfamily have recently been discovered in the placenta and fetal blood brain barrier. These include the multidrug resistance P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP). These proteins are important in protecting the fetus and the fetal brain from a large number of drugs and toxins. P-gp and BCRP are also involved in the transport of endogenous (or natural) factors including certain hormones (glucocorticoids) and nutrients (folate). As such, they may play an important role in regulating access of endogenous factors in the maternal circulation to the fetus, in normal development. Studies in human placenta and the mouse are being carried out to define the expression and regulation of P-gp and BCRP. We have recently shown the there is a marked decrease in the levels of P-gp in the human and mouse placenta with advancing gestation. Very interestingly, as placental protection of the fetus by P-gp decreases in late gestation, there is a corresponding increase in P-gp expression in the developing blood-brain barrier. P-gp and BCRP in the blood-brain barrier are critical for protecting the brain against entry of drugs and toxic factors that are present in the circulation. Up-regulation of P-gp expression in the brain in late gestation indicates maturation of the blood-brain barrier which becomes critical after birth (when the placenta can no longer provide protection). In a series of studies we have investigated the molecular mechanisms that regulate changes in drug resistance in the placenta and fetal blood brain-barrier. We have also identified novel factors that can potently modify normal drug resistance. By understanding the regulation of drug resistance during normal development we will be in a position to create interventions that can either increase or decrease sensitivity of the fetus to specific drugs. This is important when the fetus or the mother is the intended target for the therapeutic drug being administered. These studies will also help to increase our fundamental understanding of drug resistance in the blood-brain barrier after birth.

METHODS USED

Cell and tissue culture: Endothelial cells, human placental cells, human placental explant cultures, placental cells & explants

Procedures: Endothelial cells, artery on a chip method, behavioral tests, elisa, gene expression analysis, immunohistochemistry, immunocytochemistry, mass spectrometry, microarrays, proteomics, qRT-PCR, RIA, RT-PCR, siRNA, western blot, in situ hybridization, human placental cells, human placental explant cultures, in situ hybridization, epigenetics analysis.

EQUIPMENT USED

Analytical balances, benchtop centrifuge, blotting apparatus, culture hood, culture incubators, cryostat, deconvolution fluorescence microscope, departmental beta and gamma counters, digital microscope, dissecting microscope, fluorescence microscope, fresh tissue sectioning systems, gel apparatus, low- and high-speed centrifuge, low and ultralow freezers, microwave oven, mini vortexer, plate reader, real-time/thermocycler, stirrer/hot plate, water baths, image analysis

PRESENT TRAINEES

Jane Joanna Pappas (PDF)
Enrico Boise (PDF)
Lisa  Boureau (PDF)
Vasilis Moisiadis (PhD)
Stephanie Baello (PhD)
Andrea  Constantinof (PhD)
Mohsen  Javam (MSc)
Samantha Kearney (MSc)

PRESENT COLLABORATIONS

Within the Department of Physiology:
Stephen Lye
Lee Adamson
Steffen-Sebastian Bolz

Outside the Department of Physiology:
Elizabeth Azstoles, Pediatrics/Toronto
Kellie Murphy, Ob-Gyn/Toronto
Robert Levitan, Psychiatry/Toronto
Bill Gibb, Ob-Gyn/Ottawa/Canada
Moshe Szyf, Pharmacology/McGill/Canada
Michael Meaney, Psychiatry/McGill/Canada
John Challis, UBC
David Phillips, MRC/Southampton/UK
Colin Sibley, Ob-Gyn/Manchester/UK
Craig Pennell, Ob-Gyn/University of Western Australia/Australia

Committee member/officer of national/international scientific organization:
International Society of Developmental Origins of Health and Disease (DOHaD)

PRESENT GRANT COMMITTEES SERVED ON
Agency: CIHR
Committee: Endocrinology (Chair)

Recent Publications

http://www.ncbi.nlm.nih.gov/pubmed/26143962

Appointments

Department of Physiology, Obstetrics & Gynecology and Medicine, University of Toronto
Director of Research, Alliance for Human Development
Associate Scientist, Lunenfeld-Tanenbaum Research Institute, Sinai Health System