Hollow organs such as the intestines, bladder, uterus, blood vessels, and the airways that make up lungs are lined with smooth muscle cells. Normal functioning of these organs depends on the ability of these cells to contract and relax – processes that control the volume and shape of the organs and enable them to perform their various functions. When an individual has asthma, excessive contraction of the airway smooth muscle results in airway narrowing, compromising the individual’s ability to breathe. In asthmatics, airway smooth muscle has a tendency to generate more force and shorten more extensively than in individuals without asthma. This condition is further exacerbated by the fact that the muscle cells adapt to this shorter length, making it difficult for asthmatic airways to open after an attack has occurred. Leslie Chin is studying the role airway smooth muscle plays in the development of asthma. Generally, asthma research focuses on relaxing the smooth muscle cells which is typically accomplished by using an inhaler; however, it is also important to focus on preventing these muscle cells from adapting to shorter lengths. Leslie is investigating how this adaptation occurs in asthmatics and how this adaptation is prevented in healthy people. Understanding how both the mechanics of airway smooth muscle in asthma and the alterations are altered could lead to new treatments for the disease.
Research Pillar: Biomedical
Characterization of the function of the nuclear matrix protein Lamin A in the organization of telomeres and chromosomes to determine the role in the pathology of Hutchinson-Gilford Progeria Syndrome
Hutchison-Gilford progeria syndrome (HGPS) is a rare, fatal disease that affects children and causes accelerated aging. Symptoms include dwarfism, loss of body fat and hair, aged-looking skin, stiff joints and hip dislocation. Children with this disease usually die of a heart attack or stroke at an average age of 13. HGPS is caused by a mutation in the LMNA gene which encodes a protein called Lamin A. The mutation causes instability in the cell nucleus, which is believed to lead to the premature aging in HGPS. Michelle Decker is looking for differences in the way normal and mutant versions of the Lamin A protein interact with chromosomes in the cell nucleus. Research has shown that cells from patients with HGPS have shorter than usual chromosome ends (called telomeres) than are usually found in cells of other children. Telomeres normally protect chromosomes from degradation and instability. By improving the understanding of the role that Lamin A and telomeres have in Hutchison-Gilford progeria syndrome, Michelle’s research may contribute to new understandings and therapies for the disease.
Role of Myosin Va in trafficking of neuronal vesicles
Neurons (brain cells) are separated by gaps called synapses and communicate via mechanisms which enable them to send and receive signals across these gaps. Inadequate development and maintenance of synapses is associated with a number of neurological and psychiatric conditions, from epilepsy to anxiety disorders, autism and mental retardation. Neurons use axons and dendrites to communicate across synapses. Axons are long fibers that transmit impulses to other neurons. Dendrites form a network of branches that receive signals from other nerve cells. Newly-made proteins within neurons must be transported to appropriate sites in axons or dendrites for proper communication to occur. However, little is known about how these proteins are accurately relocated. Frederick Dobie is studying one of the molecules thought to be involved in protein transport (Myosin Va), which is widespread in the brain, to clarify its role in pre and post-synaptic communication. Research has shown that a mutation in Myosin Va leads to Griscelli Syndrome, a disorder which causes severe motor and neurological impairment in humans. Other CNS disorders may also result from malfunctions in intracellular transportation of the proteins that facilitate communication between neurons. A better understanding of the action of transport molecules may lead to better methods of treatment for neurological disorders.
Meiotic errors in spermatogenesis: the role of recombination and synapsis in male-infertility and the production of aneuploid sperm
About two per cent of men are infertile due to defects in sperm production. In most cases, the underlying cause is unknown. During sperm production, two similar chromosomes – microscopic bodies that carry heredity DNA – pair up and exchange genetic material in a process called meiotic recombination. Recent studies have shown that recombination rates are significantly reduced in infertile men. Infertile men are also more likely to produce sperm with extra or missing chromosomes (called aneuploid sperm). This aneuploid abnormality is the most frequent cause of miscarriage, and among live births, the most common cause of congenital malformations. Kyle Ferguson is using leading edge technology to determine if and how aberrant recombination causes infertility. He is also investigating the recombination patterns that lead to production of aneuploid sperm. This information will help identify genetic mutations that contribute to male infertility, and may lead to new therapies for the condition.
The role of dopamine in learning and memory in Caenorhabditis elegans
Dopamine is a chemical (neurotransmitter) that transmits signals between brain cells. Dopamine is involved in motor control, emotion, motivation, cognition, learning and memory. Fluctuations in the level of dopamine in the brain is associated with many conditions that involve deficits in learning and memory, including schizophrenia, Parkinson’s disease, attention deficit-hyperactivity disorder (ADHD) and drug addiction. Andrew Giles is studying how dopamine acts to produce learning and memory in C.elegans, a microscopic worm with a nervous system similar to that of humans. Andrew is examining how changes in the levels of dopamine affect the completion of learning and memory tasks. This information will help explain how dopamine functions in human learning and memory, and its role in normal and abnormal behaviours. The results could support the development of new treatments for disorders involving memory and learning deficits.
Regulation of antibiotic resistance and virulence by two-component response regulators in Pseudomonas aeruginosa
The bacterium Pseudomonas aeruginosa is a major cause of hospital-acquired infections and chronic cystic fibrosis lung infections. This pathogen is difficult to treat because it has the ability to sense and appropriately respond to changing environmental conditions. For example, it can sense and respond to the presence of antibiotics by becoming resistant, making the eradication of established infections extremely difficult. P. aeruginosa infections in cystic fibrosis patients are almost always deadly. An underlying mechanism for antibiotic resistance involves two-component regulatory systems – containing a sensor kinase and a response regulator – that enable bacteria to sense and respond to environmental signals. Two of these regulatory systems within P. aeruginosa have previously been shown to be involved in antibiotic resistance. Jamie Gooderham is determining whether other closely-related P. aeruginosa two-component regulatory systems are also involved in virulence and antibiotic resistance. To do so, he is generating bacteria defective in these systems and studying their virulence, gene expression, and responsiveness to antibiotics. These studies will increase understanding of how this pathogen adapts to environmental signals to develop antibiotic resistance. Ultimately, this will lead to more effective P. aeruginosa therapies, improving treatment outcomes for infected patients.
SHIP Down-Modulation as a Potential Approach to Protect Hematopoietic Cells During Chemotherapy or Radiotherapy
Chemotherapy and radiotherapy are currently used to treat many types of cancer. However, these treatments are not ideal because they target all dividing cells, including both cancerous and healthy cells. Blood cells, for example, have a finite lifespan and new cells are continuously being generated in the bone marrow. Unfortunately, the high doses of chemotherapy or radiation necessary to destroy malignant cells also kill these bone marrow cells. This reduces the body’s ability to replenish healthy blood cells, leading to life-threatening side effects such as anemia, infections, and uncontrolled bleeding. In such cases, the chemotherapy or radiation dose must be reduced, which, in turn, reduces the likelihood that cancerous cells will be eradicated. Melisa Hamilton is studying ways to protect blood cells during cancer treatment, with a particular interest in understanding how the SHIP protein inhibits blood cell survival. Melisa wants to determine whether reducing the level of this protein can increase cell survival during treatment. This would enable patients to withstand higher doses of chemotherapy or radiation with fewer side effects and increase the likelihood of killing the cancer cells.
Somatic and gametic loss of imprinting (LOI) in mammalian development: studies using a novel imprinted transgene on the mouse distal choromosome 7 (MMU7) imprinted region
Genetic inheritance in an offspring primarily results from the interplay of dominant and recessive genes between two parents. With certain genes, however, gene expression is parent-of-origin-specific: these genes will always be expressed from either the maternal or paternal chromosome. This process is known as genomic imprinting, which creates a mark, or “imprint”, on the chromosome. Loss of imprinting (LOI) is often studied in the context of disease, especially in cancers, but it is also a normal part of development. For example, in germ cells, imprints are erased and re-set early in development every generation, resulting in a normal period of LOI. Meaghan Jones is investigating a hypothesis that non-germ cells may also experience some normal LOI during development. She will examine the timing, stimulus and duration of LOI in germ cells and somatic cells during development. By determining the various causes of LOI in both types of tissues, she hopes to uncover factors regulating normal LOI and help alleviate the risk of imprinting defects.
Notch signalling in mammary tumorigenesis
Breast cancer is the most common cancer among Canadian women. One in nine women is expected to develop breast cancer in her lifetime, and one in 27 will die of the disease. Metastasis, or the spread of the tumour to another site, is the major cause of death. Notch receptors are cellular proteins required for normal growth and development. However an overproduction of an active component of Notch can cause abnormal cell growth, leading to tumour formation and the spread of cancer to distant sites. Iva Kulic is examining how another protein, called Slug, functions with Notch to promote breast cancer. Both Notch and Slug are found at high levels in some human breast cancers and are a sign of poor outcome. Slug prevents tumour cells from dying and allows them to detach from neighbouring cells and travel to other sites within the body – two key features in tumour development and metastasis. This research will explore whether reducing or eliminating the Slug protein will inhibit breast tumour growth and block the spread of cancer cells. Resolving whether Slug is essential in Notch-induced breast cancer could lead to new ways of preventing and treating the disease.
Activation of NR2A-containing NMDA receptor-mediated cell survival as a novel and innovative therapeutic strategy in the treatment of stroke
Stroke is a major cause of death and disability in North America. Major efforts have been placed into blocking mechanisms of excitotoxicity following stroke. Immediately after the onset of stroke, a plethora of glutamate is released in the affected area, and activation of NMDA-receptor by glutamate has been attributed to be the main cause of neuronal damage during stroke. Nevertheless, clinical studies of stroke patients given NMDA-receptor blockers have proven to be disappointing. It has been suggested that NMDA-receptor blockers are efficacious only when given prior and/or soon after stroke onset. Once the receptors and downstream death signaling cascades are activated, blocking NMDA-receptor is no longer useful. Since stroke patients often reach the hospital and receive their diagnosis several hours after stroke onset, the conventional therapeutic strategy of blocking NMDA-mediated cell death is not clinically useful. Surprisingly, our preliminary study suggested that only the NR2B subunit-containing NMDA-receptors (NR2BR) promote cell death, and paradoxically, the NR2A subunit-containing NMDA-receptors promote cell survival (NR2AR). We propose that selective activation of NR2AR-dependent cell survival may be a more effective stroke treatment strategy than blocking NR2BR-dependent cell death. In addition, because we are proposing to promote cell survival and not blocking cell death, our treatment should be effective even when administered along time after stroke onset.