MRC grants for three Memorial projects
Two research projects in the Faculty of Medicine and one in the Biochemistry Department succeeded in the latest round of grant decisions from the Medical Research Council of Canada.
At the medical school. Drs. Laura Gillespie and Gary Paterno were awarded $78,736 per year in operating funding and $14,714 for equipment over a three-year period. Dr. Christopher Kovacs will receive $50,000 per year in operating funding over a three-year period.
Dr. John Brosnan, Biochemistry, who is also cross-appointed to the Faculty of Medicine, was awarded $124,648 per year in operating funding over a five-year period.
Research on new gene
Drs. Gillespie and Paterno are members of the Terry Fox Laboratory, which is devoted to cancer research. Their project is on the characterization of a new tumour-associated gene.
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Drs. Laura Gillespie and Gary Paterno |
"Cancer cells do not know when to stop growing," explained Dr. Paterno. "The signaling circuitry that controls cell growth has gone awry and the signal to grow doesn't get switched off. To find out more about how this signaling circuitry works we are studying fibroblast growth factor (FGF). In some cells, the FGF circuitry has 'shorted out', bypassing the signal to stop growing and causing the cells to become cancerous."
Dr. Paterno said that they have recently discovered that when the FGF signal reaches the nucleus, it activates a new gene which they have named er1. "We have found that er1 is normally activated in early embryonic development, but then gets switched off. Although it's not in normal adult breast and cervical cells, it is at high levels in tumour cells from these same tissues."
The MRC funds will be used to discover how this new gene behaves. "In this way, we may be able to determine how FGF, acting through er1, can control early embryonic development in a normal state and how misregulation may contribute to cancer," said Dr. Paterno.
Studying calcium metabolism
Dr. Kovacs is a clinician scientist in the Discipline of Medicine (Endocrinology) and the Division of Basic Medical Sciences, whose laboratory is devoted to calcium and bone-related research. His MRC funding will be used to study the regulation of fetal-placental calcium and bone metabolism in genetically engineered mice.
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Dr. Christopher Kovacs |
The fetus faces a unique challenge with respect to normal calcium metabolism: maintaining a tightly controlled level of calcium in the blood that is higher than in the mother, pumping calcium across the placenta from the mother to the fetus, and calcifying the developing skeleton. Disruptions in the process can lead to such disorders as neonatal hypocalcemia and fractures, or predispose to osteoporosis later in life.
Dr. Kovacs' research will look at the unique mechanisms the fetus uses to enable it to regulate fetal-placental calcium metabolism, since the normal adult calcium-regulating hormones do not seem to be as important.
"I will be using a novel strategy in my study to compare and contrast the physiological impact on fetal calcium homeostasis of the selective removal of specific calcium-regulating hormones or their receptors through gene targeting," said Dr. Kovacs. "These genetic techniques permit the study of fetal models that cannot be created by standard surgical or pharmacological techniques."
By studying what happens when a calcium-regulating hormone or factor is absent, one can deduce what it may be doing normally when it is present."
Ultimately, the insight gained from these studies may improve the knowledge of human diseases that involve altered calcium and skeletal homeostasis. "In addition, the novel strategies used by the fetus to regulate calcium and bone homeostasis may suggest the development of alternative approaches for the management of metabolic bone disorder in adults, such as osteoporosis."
Amino acid metabolism
Dr. Brosnan is studying amino acid metabolism. His work, which has been funded continuously by MRC since 1972, is on fundamental mechanisms in metabolism and has direct applications to a number of nutritional and pathological situations.
"We are looking at what determines the rate at which amino acids are broken down in the body," said Dr. Brosnan. "That rate then determines the dietary need for protein -- if you break down amino acids very quickly, then you need a higher intake of dietary protein."
Dr. Brosnan's research has shown that the hormone glucagon, which is released by the pancreas and opposes many of the effects of insulin, is a key factor in the rate of amino acid breakdown. His laboratory has pioneered a novel means of examining these processed by using amino acids labelled with heavy nitrogen.
"With this technique, and using gas chromatography/mass spectrometry for detection, we are able to follow the fate of the nitrogen atoms of the amino acids through the body. An advantage of this technique is that heavy nitrogen is not radioactive, and can be used in human subjects, so the techniques we have pioneers in animals are directly applicable to human studies."
In the next five years, Dr. Brosnan will be examining a new hypothesis that suggested that many adult diseases such as Type 2 diabetes and hypertension, are programmed in utero. "The idea is that if the pregnant mother experiences nutritional deprivation, there may be alternations in the development of a number of organs such as the pancreas and liver, that can predispose to disease in adulthood."
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