Aneuploidy – the result of the uneven separation of two matching sets of chromosomes during cell division – is found in more than 70 per cent of cancers and is now widely accepted as a major predisposing condition to cancer initiation and progression. Benjamen Montpetit is studying the role of the kinetochore, a protein complex that is of fundamental importance to the equal separation of chromosomes during cell division. Using yeast cells as a model, his research into the components responsible for chromosome transmission will result in a better understanding of the events involved in creating aneuploid cells and will provide a mechanistic basis for understanding chromsome instability in human cancers.
Research Pillar: Biomedical
Cell fate mapping of putative neural stem cells
Disease states such as Alzheimer’s, Parkinson’s, stroke and spinal cord injury each affect the nervous system in what was once thought to be an irreversible manner. However, recent scientific evidence suggests that damaged areas of the nervous system may have their functions restored by transplantation of neural stem cells or by administration of molecules that coax the body’s neural stem cells to self-repair. To put this knowledge into practice, researchers require a better understanding of the basic mechanisms of stem cell development. Barbara Murdoch was previously funded by MSFHR to identify proteins specific to the surface of neural stem cells so she can study their growth requirements. Building on this, she is now using olfactory epithelium cells to determine the role of the protein nestin in the development of neural stem cells. She is studying which cell types express (produce) nestin and determining their pattern of expression. By understanding these mechanisms, she hopes to contribute key knowledge necessary for effective clinical applications requiring stem cell transplantation, expansion and gene or drug therapies.
Involvement of inducible nitric oxide synthase and nitrosative stress in vascular dysfunction in Diabetes
Cardiovascular complications are the major cause of morbidity and mortality in diabetes – a disease that affects millions of people worldwide. The lack of specific treatments for these complications is due, in part, to the poor understanding of the underlying cellular and molecular mechanisms, e.g., the signalling pathways that might cause malfunction, and pathways that protect normal vascular function. In diabetes, there are changes in the ability of blood vessels to constrict and relax, which in turn can affect blood flow and blood pressure. Prabhakara Nagareddy is studying how blood vessels function in diabetes and the mechanisms directly relevant to the development of vascular disease. He is exploring the vasoconstrictory role of a well-known growth receptor (epidermal growth factor receptor) pathway and the vasodilatory inducible nitric oxide synthase (iNOS) pathway in normal and diabetic arteries. By developing an understanding of how these pathways produce their effects, this research could facilitate the discovery of unique drug targets for future cardiovascular disease treatments, particularly for high blood pressure.
The role of Annexin II in airway epithelial wound repair and the effect of corticosteroids on the Annexin II regulated pathway
Asthma is an inflammatory condition of the lungs that affects a growing number of individuals in developed countries worldwide. Current research and therapies for asthma are aimed at relieving the symptoms associated with the disease rather than the underlying defect. In spite of the use of anti-inflammatory agents, asthmatics experience progressive changes in airway structure and cumulative damage to the cells that line the airways (epithelium). The accumulation of damage due to ineffective repair may in part explain the airway’s hyperresponsiveness in asthma and highlights the importance of effective epithelial repair. Ben Patchell seeks to identify molecules that normally contribute to the process of epithelial repair and apply these findings to diseases such as asthma. Specifically, he is studying glycosylation, a process in which certain molecules gain sugars to become fully functional. Glycosylation has previously been shown to be essential in the repair of normal airway cells and there are demonstrated differences between the cells of normal and asthmatic individuals. Ben has developed a method to identify the unknown protein molecules responsible for these differences. Annexin II has been identified as a novel mediator of epithelial repair and has been demonstrated on the surface of airway epithelial cells. Ben is exploring how Annexin II and its associated proteins are regulated and the mechanisms by which they regulate cellular events such as migration in both normal and asthmatic epithelium. He is also investigating the effect of steroids, the primary therapy for asthma, on each of the cellular events. This research could lead to new research strategies and new therapeutics for asthma.
Alterations in hippocampus structure and function during pregnancy and motherhood. The role of corticosterone
Pregnancy and motherhood are life-changing events that often result in cognitive and mood disturbances. Research has shown decreased verbal recall and decreased spatial ability in women during the last trimester of pregnancy. Spatial memory relies in part on the integrity of the hippocampus in the brain, and on the steroid hormone corticosterone, but little is known about the effect of pregnancy and motherhood on these processes and how they relate to memory and learning. Jodi Pawluski is investigating the relationship between corticosterone, hippocampus structure and hippocampus-mediated learning and memory during pregnancy and motherhood. In addition to advancing understanding of how reproductive experience affects neurological, cognitive and hormonal processes in the mother, she hopes her work may contribute to the development of therapies for pregnancy-related diseases such as postpartum depression.
Evaluation of small molecule therapeutics modulating excitotocity in a mouse model of HD
Huntington’s disease (HD) is a progressive neurological disorder characterized by involuntary movements, emotional disturbances and memory loss. There is currently no cure for HD, and the disease is ultimately fatal. HD is caused by a selective loss of a population of nerve cells in specific regions of the brain, particularly the striatum. Accumulating evidence suggests that overactivation of glutamate receptors (transmembrane proteins involved in communication between nerve cells), which are abundant in the striatum, might lead to the selective death of nerve cells observed in HD. Mahmoud Pouladi’s research focuses on evaluating the efficacy of small molecule therapeutics known to target glutamate receptor signalling pathways in a model of HD. His work explores whether restoring physiologic levels of intracellular calcium by modulating glutamate signalling will prevent the neurodegeneration and associated motor and behavioural deficits observed in HD. This study will further our understanding of this disease and provide insights about glutamate signalling as a therapeutic target for the treatment of HD.
Epigenetic Regulation of Natural Killer Cell Receptor Genes
The innate immune system, unlike the adaptive immune system, does not first require exposure to a foreign substance before immunity can be developed. Natural killer (NK) cells—a subset of white blood cells—make up a major part of the innate immune system. NK cells are considered a first line of defence in the body as they can recognize and destroy cells that have been altered, such as in the case of virus-infected or tumour cells and also foreign cells. This recognition is through the interaction of receptors on the surface of NK cells, with the receptor molecules called MHC class-1, expressed on the surface of target cells. The absence or alteration of numbers of MHC class-1 on abnormal target cells results in their destruction by NK cells. In both humans and mice, there is great variability in the number and combination of receptors on individual NK cells. Furthermore, it has recently become evident that the receptor repertoire of NK cells can change in response to various stimuli. Building on her previous MSFHR-funded work, Arefeh Rouhi is studying the mechanisms that control these variations among NK cells. Understanding how NK receptors are controlled is critical to the interpretation of how the repertoire is modified in response to infection and tumour cells, and the response of NK cells to mismatched bone-marrow grafts. Ultimately, this knowledge may lead to the development of methods to use the body’s own immune system to protect against infections and malignancy.
Antagonism of the p75 Neurotrophin Receptor promotes neurotrophin-mediated neural regeneration and plasticity within the injured spinal cord
Functional recovery following spinal cord injury is extremely limited, leaving individuals with limited mobility, autonomic dysfunction, and chronic pain. The lack of significant recovery following this type of injury reflects the failure of mature nerve fibres (axons) to regenerate and the incapacity of uninjured nerves to undergo compensatory growth (plasticity). Regeneration and plasticity are governed by a balance between growth-promoting and growth-prohibiting factors within the injured spinal cord. Neurotrophic factors and myelin-associated inhibitory proteins (MAlPs) both influence axonal growth through axonal receptor complexes that include the p75 neurotrophin receptor (p75NTR). MAIPs suppress axonal growth through p75NTR; neurotrophic factors augment axonal growth partly by inhibiting p75NTR. Angela Scott has found in past research that both the regeneration of injured axons and the plasticity of spared axons can be improved with the antagonism of p75NTR. Her current research explores the role of p75NTR following spinal cord injury. By determining the functional significance and clinical relevance of p75NTR antagonism, her work may lead to clinically relevant therapeutic treatments that improve functional recovery for people with spinal cord injuries.
Computational methods for array CGH analysis for improved diagnosis of human cancers
Chromosomal instability is a hallmark of tumour cells in human cancer. Regions of chromosomal instability can have various forms including single point mutations, rearrangements, whole chromosome loss or duplication, or chromosomal segments containing DNA copy number change. The alterations change the expression of cellular constituents and eventually result in cells that do not function normally. Finding regions of chromosomal instability provides important locations in the human genome that are both symptomatic and diagnostic markers of various cancers. Recently developed techniques called array comparative genomic hybridization (aCGH) have allowed scientists an unprecedented high degree of resolution to detect regions of chromosomal instability in cancer patients. The experiments produce both a high volume of data and noisy signals that are not cleanly interpretable. Therefore, robust computational techniques must be developed that can automatically identify regions of chromosomal instability. Sohrab Shah is developing computational methods and statistical models that, given aCGH data for one or more patients, can accurately and reliably detect chromosomal aberrations. His research will first evaluate this method on standard data sets where the location of the aberrations are known, and then apply the method to three large scale genomic studies to discover chromosomal locations affected in lung, brain and lymphoma tumours. He will also assess the diagnostic utility of chromosomal alterations that are recurrent across patients and develop prototype diagnostic tests that may ultimately be put into clinical practice.
ACK family tyrosine kinase may participate in the control of dorsal closure through negative regulation of Egfr
The Rho family of small GTPases in the fruit fly Drosophila are key controllers of cell shape and cell movement through their participation in signalling networks that control a variety of cellular processes. These proteins function as molecular “switches”, turning on or off the particular steps in the signal pathways to control cell shape or cell movement. The study of these molecules provides us with important medical insight since disturbance of their signalling has been implicated in a variety of disorders including cancer and a number of inherited conditions, such as mental retardation, deafness and facial deformities. These proteins have also been shown to be key regulators in wound healing. The activated Cdc42 kinases (ACKs) are proteins shown to be effectors for the Rho GTPases Cdc42, and are linked to the regulation of Drosophila Dorsal Closure (DC). DC is a well-known animal model system for studying wound healing. Previous studies have demonstrated Drosophila activated Cdc42 kinase (DACK) functions in controlling cell shape change and movement of epidermal cells during DC. Weiping Shen is using the DC as a model system to assemble signalling networks controlling the movement and shape of cells. The learning gained from these signalling pathways will shed light on their roles in human development and disease. By developing a better understanding of the mechanisms that allow signals to translate into physical movements, this research could lead ultimately to solving many genetic and developmental puzzles related to human diseases.