Kenya Fund
  2008-2009

Endowments
  W.J. Hannah

Fellowships
  2009-2010 RBC
  2007-2008 Scace
  2007-2008 RBC
  2007-2008 TD
  2006-2007 RBC
  2005-2006 TD

Grants
  2008-2009
  2007-2008
  2006-2007
  2005-2006
  2004-2005
  2003-2004
  2002-2003
  2001-2002
  1999-2000
  1997-1998
  1996-1997
  1995-1996
  1994-1995
  1993-1994
  1992-1993
  1990-1991

Research Grants Awarded in 2005-2006

Maryam Yeganegi

Government of Ontario/Pharmacia Canada Inc./Genesis Research Foundation/OBGYN Graduate Scholarship in Science and Technology at the University of Toronto, Faculty of Medicine Thesis: Effect of Lactobacilli on Cytokine Production in Intrauterine Tissues Premature birth is prevalent in today’s society and complicates 7-10% of all pregnancies. It is characterized by initiation of the labour process before 37 weeks of gestation. Preterm birth is associated with up to 85% of neonatal morbidity and mortality and may lead to behavioral and learning problems for the child, as well as emotional and financial challenges for the family. Many studies have been undertaken to explain the underlying mechanisms responsible for preterm birth, hence trying to solve what seems to be one of the biggest challenges in perinatal health care. It has been shown that the onset of labour is initiated through a signaling pathway originating from the fetus, which stimulates the uterine muscle through increased synthesis and decreased degradation of prostaglandins. 30% of preterm births are infection-mediated, some caused by Bacterial Vaginosis (BV). BV is the result of an alteration in the endogenous vaginal microflora, associated with decreased levels of certain Lactobacillus. Lactobacillus increases the production of anti-inflammatory cytokines such as IL-4, IL-10, and IL-11, interfering with the cascade leading to preterm births and inhibiting the growth and attachment of organisms causing BV. Regulatory peptide cytokines are key mediators for organizing the interaction between the immune cells such as macrophages and are also responsible for regulating a variety of cell processes. Their production is, therefore, regulated to ensure the homeostasis and effective defense against pathogens. Any failure to maintain homeostasis between the anti- and pro-inflammatory cytokines will lead to inflammatory diseases. It has been shown that BV is also associated with increased growth of harmful bacterias such as Gardnerella, causing an elevated release of pro-inflammatory cytokines such as IL-1ß, IL-2, IL-15, and TNF-a and increased prostaglandin levels. This will in turn lead to increased contractility and preterm birth. As such, the focus of my graduate work will be on cytokine profile of placental and chorion trophoblast cells with and without lipopolysacchoride and in the presence or absence of Lactobacilli preparations. Hypothesis: L. rhamnosus GG and GR-1 treated trophoblast cells secrete inhibitory factors that suppress and modulate the expression of pro-inflammatory cytokines and up-regulate the anti-inflammatory ones once activated by LPS. It is hoped that such study would contribute to the long term objective, which is to demonstrate that restoring a vaginal microflora rich in Lactobacilli will interfere with the pathogenesis of BV and the cascade leading to preterm birth.

John Sun

Government of Ontario/Pharmacia Canada Inc./Genesis Research Foundation/OBGYN Graduate Scholarship in Science and Technology at the University of Toronto, Faculty of Medicine Thesis: The Effects of Fetal IGFBP-1 Overexpression on Cardiac Function and Anatomy Insulin-like growth factors (IGFs) are essential regulators of fetal growth and are controlled by the inhibitory effects of IGF binding proteins (IGFBP-1 to 6). IGFBP-1 is the most important regulator of IGFs during fetal and neonatal development. High blood levels of IGFBP-1 during fetal development leads to low birth weight in humans and animals, which consequently leads to significantly increased risk of heart disease morbidity and mortality in adulthood. IGFBP-1 likely plays an important role in heart development. Unfortunately, very little is known about the effects of IGFBP-1 on the fetal heart and whether such effects have long-lasting consequences on the adult cardiovascular system. In order to mimic low birth weight in humans, a fetal IGFBP-1 overexpressing mouse model was created. A mouse model was chosen because of their low cost, fast reproductive rate, and high genetic and physiologic similarity to humans. Using such model, our lab has demonstrated that IGFBP-1 overexpression during the fetal period alters cardiac development and leads to permanent impairments in cardiac function and anatomy in adulthood. Such impairments are likely to increase risk of acquiring heart diseases. The long-term goal of this study is to uncover the mechanisms that underlie the correlation between low birth weight and increased incidence of adulthood heart diseases. When such mechanisms are uncovered, heart disease treatments will be able to target fetuses and newborns to prevent adulthood cardiovascular diseases.

Jocelyn Ray

Government of Ontario/Pharmacia Canada Inc./Genesis Research Foundation/OBGYN Graduate Scholarship in Science and Technology at the University of Toronto, Faculty of Medicine Thesis: Role of Matador in Trophoblast Proliferation During Human Placental Development (MSc.) During pregnancy, the development of the fetus relies primarily on one organ – the placenta. The role of the placenta is to perform a multiplicity of functions, which in adulthood are accomplished by an extensive network of organs. It acts as a barrier to disease, produces essential hormones and is the primary site of gas and nutrient exchange between the mother and fetus. Abnormalities in placental development or function can therefore be extremely deleterious. Trophoblast cells are the cells responsible for the formation and function of the placenta. Alteration in the trophoblast cell rheostat with respect to proliferation, differentiation or cell death may therefore lead to the possibility of improper placental function. Pre-eclampsia and molar pregnancies are two examples of trophoblast related disorders that are associated with improper placentation. Thus far however, the cause of these disorders is not fully understood. Currently both disorders are defined by similar clinical features including hypertension, proteinuria, and edema. Furthermore, both molar and preeclamptic placentae are characterized on the cellular level by an immature, more proliferative, trophoblast phenotype. This has lead many to believe that the study of molecules involved in trophoblast cell cycle and proliferation will provide further understanding of how improper placentation and disease are associated. Previously, Matador (Mtd), a pro-apoptotic protein, was identified as a key player in the regulation of cell death in reproductive tissue. A specific role of Mtd in placentation has been further supported by the recent discovery by the Caniggia lab of a novel spliced variant of Mtd that is unique to the placenta. Of clinical importance, the level of Mtd was found to be significantly increased in cases of severe early onset pre-eclampsia. Moreover, the expression of Mtd was found to be highly expressed early in gestation when cell death is low and proliferation is high. There is now increasing evidence pointing to the possibility that some proteins involved in cell death may have a dual function and may also play a role in cell cycle control. This has been a recent area of study for the lab and is the basis of my research project. Hypothesis: Mtd not only regulates cell death, as previously determined, but may also contribute to trophoblast cell proliferation during early placental development.

Amita Kapoor

Government of Ontario/R. Howard Webster Foundation/Genesis Research Foundation/Physiology Graduate Scholarship in Science and Technology at the University of Toronto Thesis: Prenatal stress modifies HPA axis activity and behaviour throughout life: Mechanisms of programming Epidemiological evidence indicates that poor fetal growth is associated with an increased risk of a number of adult diseases, including cardiovascular disease and depression. The link between fetal growth and disease susceptibility involves the process of fetal programming. This is a process by which a stimulus encountered during critical windows of development can have permanent effects on the structure and/or function of physiological pathways, subsequently leading to pathological consequences in adult life. Glucocorticoids (GC), the end product of hypothalamic-pituitary-adrenal (HPA) axis activation are postulated to be a primary mediator of fetal programming. Studies have revealed that exposure to GC in utero can produce many of the symptoms observed in adults that had poor prenatal growth, including permanently altered basal and stress-induced HPA axis activity. Chronically elevated levels of endogenous GC in the body can have a number of adverse effects including decreased growth, immuno suppression, and altered cardiovascular and behavioural regulation. Modified regulation of the HPA axis, as occurs in the process of fetal programming, also impairs the ability of the organism to cope with physical and/or psychological stress. Exposure to a stressor during pregnancy results in activation of the maternal HPA axis and consequently an influx of excess endogenous GC of maternal origin to the fetus. Studies have shown permanent and sex-specific effects on pituitary-adrenal function and stress-related behaviour in offspring whose mothers were exposed to stress during pregnancy in critical windows of fetal brain development. Further, female offspring demonstrated an interaction between programming of the HPA axis, behaviour and stage of the reproductive cycle. The aim of this study is to understand the relationship between an altered maternal environment and modified neuroendocrine and behavioural function in adulthood. Specifically, how a moderate maternal stress during pregnancy affects HPA axis activity and interactions with other physiological pathways, such as the sympathetic nervous system and the hypothalamic-pituitary-gonadal axis. In addition, we will identify how these changes modify anxiety and attention related behaviours in offspring. We hypothesize that prenatal stress will have profound effects on HPA axis function in the adult, but the specific nature and severity of the effect will be dependent on gender and the timing of the stress as well as by interactions with other neuroendocrine pathways. This study will dissect and determine a number of the mechanisms involved in the process of fetal programming, which represents a key link between adverse intrauterine environment and susceptibility to disease in adult life.