Key Interests:

• Regulation and plasticity of neuroendocrine systems during development.
• Fetal protection against drugs and toxins

Current Research Interests:
Programming of HPA function and Behaviour
A major research focus of the lab 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. However, there is little information concerning the effects of early glucocorticoid exposure on the developing brain. With respect to nutrient restriction, it is common for women particularily 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 undernutrion during pregnancy lead to transgenerational influences on HPA function and behaviour. We are now investigating the mechanisms involved in this process. We hypothesize that these include altered maternal adaptation to pregnancy and epigenetic modification.

Role of Drug Resistance Proteins in Pregnancy: Fetal Protection
A group of transporters in the ATP binding cassette (ABC) superfamily have recently been found in the placenta including the multidrug resistant gene product 1 (Mdr-1) also known as P-glycoprotein (P-gp) and Breast Cancer Resistance Protein (BCRP). These proteins are potentially capable of protecting the fetus from a large number of drugs and toxins. Mdr-1/P-gp is also involved in the extrusion of various steroids including certain glucocorticoids and may therefore play an important role in regulating fetal access of glucocorticoids. Studies in human placenta and the mouse are being carried out to define the expression and regulation of Mdr-1/P-gp and BCRP. We have recently shown the there is a marked decrease in the expression of placental Mdr-1/P-gp in the human and mouse placenta with advancing gestation which may be regulated by the decrease in progesterone levels seen in the latter species.

Diabetes and the HPA axis
Another research focus in the laboratory is to establish the changes in HPA function that occur in both Type I and Type II diabetes and how such changes develop with disease progression. These studies are being carried out in collaboration with Dr Mladen Vranic. In these studies, we are using both streptozotocin treated rats (a model of Type 1 diabetes) and ZDF rats (a model of Type II diabetes). The goals of these studies are to initially understand the changes in HPA function that occur in diabetes, but also to establish the potential role of altered function in the etiology of the disease process.

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Research Collaborations:

• Professor Bill Gibb: University of Ottawa
• Professors John MacDonald and Mladen Vranic: University of Toronto
• Professors Michael Meaney and Moshe Szyf: McGill University
• Professors Mark Hanson and David Phillips
• Professor Mark Kilby: University of Birmingham, UK
• Professor Vicki Clifton: University of Newcastle, Australia

Research support:

The Canadian Institute of Health Research
Natural Sciences and Engineering Council of Canada
British Heart Foundation
Juvenile Diabetes Foundation