Alzheimer’s disease (AD) is the most common neurodegenerative disorder leading to dementia, affecting approximately 10 per cent of the Canadian population over the age of 65. One of the pathological hallmarks of AD is increased deposition of the beta-amyloid protein, which forms amyloid plaques in the brains of AD patients. This is caused by dysfunction of the BACE enzyme, which regulates processing of the amyloid precursor protein to generate beta-amyloid proteins. Levels of the BACE enzyme have been shown to be elevated in Alzheimer’s. Philip Ly is interested in studying the underlying molecular mechanisms regulating the BACE enzyme expression and activity. He is studying a region of the BACE gene called the BACE promoter. This region has been demonstrated to be important for BACE expression. However, the regulations at the level of BACE gene transcription – the first step in the expression of the genetic information – remain elusive. Using a series of molecular and biochemical approaches, Ly is examining the transcriptional controls that regulate BACE gene expression in neurons. He is also examining if specific mutations in these transcription factors affect BACE expression and contribute to AD pathogenesis. Ly’s research will be the first to thoroughly characterize the transcriptional regulation of the BACE1 and the role of abnormal gene expression in AD pathogenesis. In addition to providing much needed information regarding signal transduction in amyloid precursor protein processing, these studies have important pharmaceutical implications, such as potential development of BACE enzyme inhibitors to improve treatment of Alzheimer’s disease.
Year: 2008
T Cell Therapy of Breast Cancer; Challenges and Opportunities
T cell therapy is a promising approach in cancer treatment that aims to use the body’s own immune system to rid itself of cancer. The therapy involves isolating T cells that react to the tumour from a patient’s blood, expanding their numbers in culture and infusing them back into the patient, with the expectation that the T cells will recognize and destroy cancer cells throughout the body. This approach has yet to be applied clinically to breast cancer. MSFHR funded Michele Martin’s early PhD work using an innovative mouse mammary tumour model to study this approach for future use in human breast cancer. By infusing tumour-reactive T cells, she has been able to induce complete tumour regression of about 37 per cent of tumours, an unprecedented result compared to other forms of immunotherapy. However, the remaining tumours show partial regression or no regression at all. Martin now seeks to understand why some tumours are resistant to this treatment. Intriguingly, while all regressing tumours demonstrate heavy infiltration with T cells after treatment, many non-regressing tumours show no infiltration at all. Martin’s hypothesis is that many resistant tumours are able to physically exclude T cells. Her research will determine the molecular factors behind the physical mechanisms contributing to a tumour’s exclusion of these T cells, and test whether she can disrupt the tumour environment to facilitate the effective infiltration of T cells. The information gathered from Martin’s genetic analysis of infiltrated and uninfiltrated/resistant tumours will provide valuable data for defining the molecular barriers to T cell infiltration, and could point to ways to overcome these barriers.
Identification and therapeutic modulation of protein targets in dysfunctional innate immune networks associated with hyperinflammation and microbial susceptibility in cystic fibrosis and inflammatory …
Inflammation is a normal biological response initiated by the immune system to help control and contain infections. Inflammatory diseases occur when defects arise in the immune system pathways that co-ordinate either the detection of pathogens, or the subsequent biological response. Single defects in various critical points on these pathways can lead to profoundly abnormal biological outcomes. When defects in critical points in these immune networks are present, two different scenarios with similar outcomes can occur. In some instances, this can result in a response that is insufficient (hypoinflammatory) for clearing foreign microbes from the body, increasing the risk of lethal infections. Alternately, the inflammatory response can be overly robust (hyperinflammatory), leading to chronic inflammation and tissue damage that impairs the immune response. Examples of diseases with hyperinflammatory phenotypes include, cystic fibrosis (CF) and inflammatory bowel disease (IBD). Matthew Mayer is studying the immune systems of children and adults with these diseases. His goal is to identify new proteins in these dysfunctional inflammatory pathways that could serve as potential drug targets. In addition to treating these immune diseases, such drugs could also be used to treat bacterial infections in otherwise healthy individuals by enhancing their immune systems. This research could lead to new therapies for patients who suffer from inherited hyperinflammatory disease. It could also advance the discovery of new, non-antibiotic drugs that could be used to fight off bacterial infections.
Spinal cord segmentation and analysis for understanding multiple sclerosis
The spinal cord is a key component of the central nervous system, acting as a relay to convey information between the brain and the rest of the body. A number of diseases affect the spinal cord, including multiple sclerosis (MS). MS affects more than 240 Canadians per 100,000, and is suspected of shrinking the spinal cord. In fact, recent studies have shown a strong correlation between spinal cord atrophy and disability related to the advancement of the disease. Spinal cord analysis, conducted with magnetic resonance imaging (MRI), is an important tool for detecting and measuring disease progression. This requires cross-sectional segmentation of the image, where specific points that correspond to the spinal cord are identified and measured over time. Most current methods require some manual intervention by radiologists; this is time-consuming and increases variability in the measurements. Chris McIntosh creates software for accurately analyzing tubular structures in the body – such as blood vessels and airways – using MRI and computed tomography. His current focus is on employing MRI to accurately measure and analyze spinal cord atrophy in patients with MS. Building on a preliminary study on automatic spinal cord segmentation, McIntosh is fine tuning the technology through additional validation, ensuring the results correspond with clinical measurements. He will then segment larger data sets with minimal user-interaction and perform analysis to see if the findings correlate with disease progression. A fully-automatic, computerized system would reduce variability seen with manual intervention, resulting in more accurate and useful spinal cord analysis. It also has the potential to free up radiologists’ time for other clinical work.
Intravesical mucoadhesive nanoparticulate drug delivery systems for application in bladder cancer
Urinary bladder cancer is one of the most commonly diagnosed malignancies in North America. The great majority of cases are superficial carcinomas, where the tumour is confined to the inner layer of the bladder wall. The most common treatment method is known as transurethral resection, which involves the surgical removal of tumour nodules from the bladder wall. However, there is a high rate of tumour recurrence after this surgical procedure. Intravesical chemotherapy, which involves instillation of one or more chemotherapeutic agents into the bladder following resection, has become the treatment of choice for superficial carcinoma. Unfortunately, the major limitation of this treatment is the rapid and almost complete washout of the drugs from the bladder on first void of urine, and low exposure of chemotherapeutic agents to the tumour sites. This can lead to treatment failure. Although drug treatments via bladder instillation following resection have decreased tumour recurrence rates, overall mortality rates for bladder cancer have not changed in Canada over the last several years. New approaches are needed to treat this type of cancer. Clement Mugabe is working to develop formulations of drugs that are not easily flushed out of the bladder. This can be achieved by creating drugs in the form of mucoadhesive nanoparticles –so tiny and sticky. Mucoadhesive nanoparticle formulations have the potential to adhere to the bladder wall, increase drug uptake into bladder tissue and thereby increase the effectiveness of drug treatment. Mugabe’s research will lead to novel formulations, and new information about the factors that influence uptake of drugs into the bladder wall.
Examining the role of N-linked glycosylation on the maturation and cell surface trafficking of hyperpolarization-activated cyclic nucleotide-gated (HCN) pacemaker channels
Cardiovascular disease remains the number one killer in British Columbia. These diseases include cardiac arrhythmias, which cause the heart to beat too slowly, too quickly, or in an uncoordinated fashion. Arrhythmias arise from dysfunction of the heart’s natural pacemaker: the sinoatrial node. The sinoatrial node consists of a group of cells responsible for generating the electrical impulse that controls normal rhythmic contraction and relaxation of the heart. In order to generate these electrical impulses, these cells possess a group of proteins known as ion channels. These proteins allow ions to selectively cross the cell membrane barrier, generating an electrical impulse that spreads to neighbouring cells. One particularly important family of ion channels are the HCN or ‘pacemaker’ channels which are responsible for generating the spontaneous activity of the sinoatrial node. The assembly and trafficking of these channels to the cell membrane is vital for ensuring our hearts beat in a regular fashion. How the cell accomplishes this task remains an unanswered question. Hamed Nazzarisedeh’s research attempts to uncover the underlying mechanisms that help regulate or contribute to the trafficking of HCN channels in the heart. Specifically, he is examining the role in which N-linked glycosylation of these proteins may factor in this regulation. His research will contribute to further our knowledge about how various forms of cardiovascular disease associated with HCN channel disruption arise in the heart. Ultimately, this work could aid in the discovery of novel treatment strategies.
Investigating the molecular mechanisms of micrometastasis and tumour dormancy in pediatric sarcoma
Sarcomas are an aggressive type of childhood cancer arising from bone or soft tissue. Despite advances in cancer treatment, sarcomas remain a deadly disease because of their tendency to spread throughout the body (metastasis). Following cancer surgery to remove a malignancy, remnant sarcoma cells are often able to remain dormant in the body for months or years, in spite of efforts to eradicate them with chemotherapy. When such therapies are ineffective, these hibernating cells may revive and regrow as deadly metastases. Under laboratory conditions, cultured cancer cells are able to survive for long periods in the form of multi-cellular clusters called “”spheroids””. Interestingly, these spheroids also appear to enter a hibernation state, with cancer cells trading away their ability to grow rapidly in favour of the ability to survive for long periods. The cells use their “oncogenes” to suppress the expression of their growth-promoting genes, despite the fact that oncogenes are normally known for their cancer-promoting properties. It is believed that cancer cells and their oncogenes target a new set of genes to drive this hibernation. Tony Ng is screening all human genes for ones important in maintaining this hibernation. Using a technique called gene expression profiling, he will determine which genes become more active when cancer cells hibernate. He is also studying two genes, TXNIP and YB-1, which appear to be important for spheroid survival and dormancy. Laboratory results will be validated using clinical samples of dormant tumour cells from childhood cancers. Ng hopes that the genes identified in these studies will become the basis of chemotherapies to specifically kill these hibernating cells, resulting in therapies that are more effective and less toxic to patients.
Spatial characterization of brain activation in Parkinson's Disease research
Parkinson’s disease (PD) affects 100,000 Canadians, and this number is expected to increase with the aging of the population. Primary symptoms include tremor, rigidity, slowness of movement, and posture instability. These motor disabilities are believed to be associated with the premature death of dopamine-secreting cells in the brain region Substantia Nigra pars compacta. However, the cause of this premature cell death is unknown, and symptoms often do not emerge until 80 per cent of the dopaminergic cells are lost. Detecting the onset of PD thus remains a major challenge, hindering the development of a cure. It is believed that substantial compensation occurs in the brains of PD patients, obscuring the early effects of disease. Therefore, current clinical assessments that rely on symptom severity may not provide an accurate measure of disease progression. Instead, it is predicted that abnormal brain activity changes will emerge long before substantial dopaminergic cells are lost. Thus, altered brain activity may serve as a more useful marker than symptom severity for diagnosing and treating PD. In order to disentangle compensatory mechanisms from disease effects, Bernard Ng is comparing the brain activity of PD patients at similar stages of disease progression, but with varying degrees of symptom severity. Specifically, he is using functional magnetic resonance imaging (fMRI),to study diseased-induced changes in brain activity within specific brain regions as well as changes in connectivity between brain regions. To more elaborately characterize brain activity, he is employing novel statistical spatial descriptors to examine the spatial distribution of regional activity in additional to the traditionally-employed intensity measures. By incorporating spatial information in this combined approach, better distinctions between compensatory mechanisms from disease effects would be enabled. Ng’s research aims to provide more accurate diagnosis of disease progression in PD patients, better assessment of medication effectiveness, and ultimately earlier PD detection.
Biological role of IL-7Ralpha Y449-dependent and -independent signals in T cell development and function
The molecule interleukin-7 (IL-7) is an important regulator of the development and signalling function of T cells, the white blood cells involved in fighting off infection and coordinating an efficient immune response. Loss of IL-7 signalling in humans results in a complete lack of T cells, demonstrating the necessity of IL-7 in the development of these important cells. After T cells mature, they circulate through the blood, searching out invading pathogens, mounting an immune response and clearing the infection. This process generates specialized memory T cells, which are able to mount a stronger and more efficient immune response upon subsequent encounters with the same pathogen. Memory cell development is the basis of vaccination, which serves to “prime” the immune system to ward off infections. Growing evidence indicates that not only is IL-7 essential in the development of these memory T cells, but that its overproduction is also implicated in a number of immune system cancers. Lisa Osborne was previously funded by MSFHR for her early PhD research training. She is now continuing her studies of IL-7. Using a number of genetic models of IL-7 signalling, Osborne will clarify the IL-7 mediated biochemical pathways that are involved in a number of T cell processes. She aims to demonstrate which molecule or pathway is primarily involved in the de-regulated growth of T cells that leads to cancer. Ultimately, this research could guide the development of vaccines that rely on the generation of memory T cells against a particular pathogen. Her work will also provide insights into the development of immune system cancers, and potentially a novel treatment approach.
Endogenous cell replacement: progenitor characterization and promotion of oligodendrocyte differentiation and remyelination in the central nervous system by attenuating myelin inhibition
White matter is the part of the nervous system composed mainly of nerve fibres covered by a lipid-dense sheath of myelin. Myelin is produced by cells known as oligodendrocytes, and is responsible for increasing the speed of electrical impulses throughout the nervous system. White matter disorders, such as multiple sclerosis (MS) and spinal cord injury (SCI), comprise a devastating group of conditions that affect millions of people around the world. Although these disorders may have different features, they are all characterized by myelin damage that will not sufficiently repair (remyelinate). While the exact cause of this insufficient remyelination is unknown, one thing is clear: for myelin repair to occur, oligodendrocyte precursor cells (OPCs) need to proliferate and migrate to areas of demyelination, to differentiate, and to then remyelinate denuded neurons. While the transplantation of cells with the potential to myelinate is feasible, there are significant barriers for effectively translating this technology into clinical treatment. An alternative strategy is to activate precursor cells within the host tissue (endogenous cells) to mobilize and promote repair. Jason Plemel was previously funded by MSFHR for his work studying oligodendrocyte transplantation following spinal cord injury. He is now exploring the dynamics of cell-based repair via endogenous cells. He is studying the capacity of oligodendrocytes to self-renew and replicate under normal and disease conditions. He is also investigating possible inhibitory signals at the region of damage that could inhibit endogenous repair, and whether these signals could be blocked to promote remyelination. Plemel anticipates that this work could ultimately lead to new targets for drugs that promote regeneration of myelin in a number of white matter disorders.