Genes are the basic blueprints used by the cells in our body. When a gene is modified, the cells in our body can be affected; in the worst case, this can cause a disease. A researcher can often be faced with several candidate genes to study in relation to a particular disease, and choosing the genes with the best potential for discovery is important for making the best use of research resources. Around the world, researchers are studying thousands of different genes to understand their roles in health and disease states. Their findings – in the form of abstracts and annotations – are captured in a variety of databases. However, this vast source of biomedical literature is an under-utilized resource. Powerful computational biology methods are required to allow researchers to mine this information. Warren Cheung is developing an automated system that can examine the available biomedical literature and quantitatively determine which genes are most likely involved in a particular disease. Not only will the system identify previous relevant findings, its integration of data and annotations from many studies is expected to identify previously unknown associations between genes and diseases. Cheung’s research will initially focus on the involvement of transcription factor genes in brain diseases and cancer. However, the techniques developed and tested will be easily adaptable to all types of genes and diseases. Cheung’s award is jointly funded by MSFHR and the Down Syndrome Research Foundation. With the ability to automatically look at all the papers that have been published on genes and their functions, this system will make unbiased predictions and previously unknown linkages. This promises to be a powerful tool for understanding genes and disease.
Year: 2008
Functional significance of adult hippocampal neurogenesis
The hippocampus is critically important for learning and memory and is one of only two brain regions than can produce new neurons in adulthood. There is some evidence that the addition of new neurons (neurogenesis) in the hippocampus is involved in or may even be required for the normal functions of this region. The rate of neurogenesis declines with age. It is widely accepted that aging is also associated with a decrease in memory performance, especially on the types of tasks that require the hippocampus. Decreased neurogenesis has been proposed as one possible factor that may reduce the efficiency of hippocampus-mediated learning and memory. And while there is believed to be a relationship between hippocampus-dependent learning and cell proliferation and survival, it’s not known What exactly this relationship is: whether neuronal growth affects hippocampus-dependent learning, or whether hippocampus-dependent learning affects the rate of neurogenesis. Other studies also suggest there may be a critical cellular age for new neurons when their survival can be altered. However, given the many conflicting studies in the literature, it is unlikely that there is a simple relationship between level of neurogenesis and memory performance. Jonathan Epp is exploring these various factors to determine the processes by which hippocampal neurogenesis occurs in adulthood, and the importance of neurogenesis to learning and memory. Using animal models, he will clarify whether cell survival can be enhanced at all times or whether there is a critical cellular age during which survival altering factors may have an impact. Epp hopes that by developing a better understanding of these relationships in the brain, this knowledge could be applied to generating therapeutic strategies for dealing with memory loss associated with aging, dementia and brain injury
The development and application of algorithms for interpreting next-generation Solexa sequencing data: creation of a genome-wide breast cancer mutation map
Breast cancer is the most common malignancy in North American women, with more than 20,000 new cases diagnosed each year in Canada. Promising new treatments like Herceptin take advantage of genetic changes that occur in breast cancer cells, which can be detected by assessing specific tumour biomarkers. This approach is possible thanks to the successful sequencing of the human genome and the development of faster, cheaper sequencing technologies. One such technology is the Illumina 1G, a sequencing platform that can sequence a full genome for medical purposes in a matter of weeks. However, this new technology requires the development of new methods for the analysis and interpretation of the output. Anthony Fejes is demonstrating the utility of these new sequencing technologies by applying them to the study of breast cancer. By fully sequencing the genome of breast cancer-derived cell lines, he will create a genetic “map” that identifies the location and nature of the changes underlying the transformation of healthy cells into cancer cells. He will then validate the maps by identifying specific genetic errors that contribute to the development of cancer, and attempt to identify currently available drugs that can be re-purposed to target these broken cellular elements. This combination of sequencing, computational analysis, and drug candidate testing provides a single “”genome-to-therapeutic”” work flow, demonstrating a method that can be applied to the development of personalized medicines. Fejes’ research will also allow researchers to find new approaches to the treatment of cancers, through development of a technique that can be applied to other genetic disorders.
The role of SHIP in the development and function of myeloid immune suppressor cells
An important role of the immune system is to identify and eliminate tumour cells. When a tumour first forms, the immune system recognizes it as foreign and generates specialized T cells to attack and kill it. However, tumours have evolved a number of mechanisms that prevent the immune system from being able to function properly, resulting in cancer progression. One of the mechanisms by which tumours escape from the immune system is by secreting chemicals that promote the generation of cells that inhibit T cells from carrying out their normal functions. The presence of these suppressive cells is one of the most common reasons current cancer therapies fail. Melisa Hamilton is investigating a specific subset of these suppressive cells, called myeloid immune suppressor cells (MISCs). Previous research has shown that the protein known as SHIP is important in regulating the survival and proliferation of myeloid cells (white blood cells). Hamilton’s research is focused on investigating the specific role SHIP plays in MISC development and function. With a better understanding of how tumours stimulate the development of MISCs and how these cells suppress the immune system, researchers can design targeted therapies to prevent the formation and function of MISCs. These therapies would greatly increase the ability of the immune system to attack and eradicate tumours and would be especially effective in combination with current cancer immunotherapy treatments to improve cancer patient outcomes.
Analysis of a carbohydrate active pneumococcal virulence factor
While the bacterium Streptococcus pneumoniae is found in 10-40 per cent of healthy people with no ill effects, it is the cause of common diseases including pneunomia, meningitis, and ear infections. Unfortunately, more and more penicillin-resistant strains of S. pneumonia are becoming prevalent, and these strains are also developing resistance to other antibiotics. There are still a few antibiotics available to treat S. pneumoniae, but resistance to these drugs will also certainly emerge. New, more effective ways to treat bacterial infections are urgently required. Bacteria have adapted the ability to use different carbohydrates, or sugars, for a number of biological processes such as metabolism. S. pneumoniae has a number of protein enzymes devoted to carbohydrate metabolism, including a pathway dedicated to degrading (breaking down) the sugar fucose. Certain proteins in this pathway have been found to be important in some aspect of S. pneumoniae infection and disease. Melanie Higgins is focusing her research on a protein called GH98. GH98 is found on the outside of the bacteria and is thought to be the first step in this fucose degradation pathway. In order to better understand how this enzyme works, Higgins will first determine the three-dimensional structure of GH98. From these structures, she will develop synthetic inhibitor molecules that keep GH98 from functioning. Her work will answer whether S. pneumoniae can still infect host cells and spread disease in the absence of GH98. If these inhibitors are proven effective, they could become a novel treatment for S. pneumoniae infections, providing clinicians more options for treating a number of bacterial diseases.
ZIP-5/Bach1 antagonizes SKN-1/Nrf2 in development and longevity
Many of the genes involved in aging are also involved in embryonic development. These same genes have been linked to cancer development (carcinogenesis). An example of such a gene is daf-2, which is the worm version of the human insulin and insulin-like growth factor receptor. When this gene is mutated in worms (C. elegans), they live twice as long. Victor Jensen studies genes regulated by daf-2 in order to find new genes implicated in longevity. He has identified a gene called zip-5 that, when mutated, allows worms to live 25-35 per cent longer and remain healthier. zip-5’s ability to extend longevity depends on the function of another gene called skn-1. SKN-1 has several functions: it contributes to embryonic gut development, it regulates stress response and is implicated in increased longevity that results from dietary restriction. The human counterpart to SKN-1 is called Nrf2, which regulates stress resistance in human cell lines. Nrf2 also provides a chemoprotective effect against carcinogenesis, injury and inflammation. The action of Nrf2 is opposed by a gene called Bach1 – the human counterpart of the worm zip-5 gene. Inhibiting Bach1 allows for easier activation of Nrf2 target genes, resulting in a stronger chemoprotective effect in cancer. Jensen’s research genetically characterizes this antagonistic relationship and identifies the novel role of zip-5 in longevity and development. He is working to determine whether the Bach1/Nrf2 relationship is parallel to the zip-5/skn-1 relationship in C. elegans, and whether it explains zip-5’s effect on longevity. He hopes his research will reveal a new role for zip- 5/Bach1 in development and longevity, and open the door to new studies looking at how Bach1 inhibition affects carcinogenesis and aging.
Somatic and gametic loss of imprinting (LOI) in mammalian development: studies using a novel imprinted transgene on the mouse distal chromosome 7 (MMU7) imprinted region
Genetic inheritance 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. Gametes are reproductive cells, such as sperm or eggs, which contain a single set of chromosomes. During their maturation, their imprints are erased then re-established. Between the erasure and re-establishment phases is a transitional loss of imprinting (LOI) state. Problems with the erasure or re-establishment of imprints in gametes can result in a number of human genetic disorders, including Prader-Willi, Angelmann, Silever-Russell, and Beckwith-Wiedemann Syndromes. In non-gamete tissues, on the other hand, imprints are generally thought to be maintained throughout life and LOI is often considered to be an abnormal condition. Both loss of epigenetic marks and loss of parent-specific gene expression are observed frequently in many types of cancers, but whether this is a cause or an effect of this abnormal growth is unclear. Meaghan Jones was previously supported by MSFHR for her early PhD studies in genomic imprinting. She is now working to determine more about what causes LOI events in both gametic and non-gametic tissues. She is using a model of Beckwith-Wiedemann Syndrome to determine when LOI occurs in cells, with the hope of pinpointing factors that can cause LOI. An understanding of normal LOI in development could help alleviate the risk of imprinting defects, and could improve effectiveness of medical technologies including assisted reproductive technologies, stem cells, nuclear transfer, and cloning.
Studies toward the total synthesis of the analgesic natural product chimonanthine and its analogues
A major area of concern for Canada’s health system is the treatment of chronic pain, which affects more than 18 per cent of Canadians and costs the health system close to $10 billion per year. More people are disabled by chronic pain than cancer or heart disease. New structurally-novel analgesics (painkillers) with unique modes of action have proven promising. One class of these molecules are the pyrrolidinoindolines, which are alkaloids (naturally occurring compounds produced by living organisms, many known for their medicinal properties). The alkaloid (-)-chimonanthine has recently been extracted from the leaves of the wintersweet, a flowering plant originating from China. This compound has been found to exhibit analgesic effects. Unlike other opiods, such as cocaine, heroin, morphine, and codeine, chimonanthines do not possess addictive properties. Using novel techniques in synthetic chemistry, Baldip Kang is working to synthesize (-)-chimonanthine. This work is a precursor to developing analogues for this compound – drugs that differ in minor aspects of molecular structure from the parent drug, synthesized so that they have more potent effects or fewer side effects. He’s focusing on determining the most efficient and cost-effective way to synthesize the molecules. He and colleagues will collaborate with a pharmaceutical company to test the analogues in pre-clinical trials, determining modifications to the structure that will further enhance the drug’s effectiveness. Through the efficient synthesis of (-)-chimonanthine and its analogues, Kang’s research promises new ways to treat chronic pain ailments.
The physiological role of P-glycoprotein in the gastrointestinal absorption of cholesterol
Cardiovascular disease (CVD) is the leading cause of morbidity and mortality among Canadians, accounting for an estimated 36 per cent of premature deaths. The majority of these CVD-related deaths result from ischemic heart disease (insufficient blood supply to the heart), which is often caused by plaque building up on the inside of blood vessels (atherosclerosis). As tobacco use has declined, elevated low-density lipoprotein (LDL) cholesterol levels have emerged as the major risk factor for the development of atherosclerosis. Treatment of elevated cholesterol has traditionally involved a drug regime of blood cholesterol-reducing statins, coupled with diet and lifestyle changes. However, increasing research evidence is driving health agencies to further lower their recommended target levels for low-density lipoprotein (LDL) cholesterol. These reduced levels may not be achievable with traditional interventions, requiring the development of new combination therapies. Inhibiting the absorption of cholesterol from the gastrointestinal tract is an attractive target for combination therapy with statins. Stephen Lee is investigating a transporter protein that is produced in the intestinal tract during the process of cholesterol absorption and processing. While several preliminary studies have implicated this protein in the cholesterol absorption process, none have investigated how this process is affected by diet. Stephen will examine the role of the protein on the absorption of cholesterol among mice fed one of four specific diets with precise fat and cholesterol contents. The proposed research may lead to the discovery of a new pharmacological target for future therapies that work with statin treatments to reduce cholesterol levels.
Identification of causal genetic alterations involved in the progression of epithelial cancers
Of the 227,000 newly diagnosed cancer cases in Canada in 2007, approximately 80 per cent were some type of carcinoma. Carcinomas (epithelial cancers) include a vast array of common cancers such as lung, breast, prostate, colorectal, oral, esophageal and cervical cancers. Patients with early stage cancer show the best response to therapies and exhibit the greater survival rate compared to those with the advanced stage disease. However, with current screening techniques, the majority of patients present with advanced stage disease at the time of diagnosis, limiting treatment options. The disruption of genes is responsible for cancer development. However, the accumulation of gene disruptions during cancer progression makes it difficult to distinguish which disruptions are the initiating events in this process. The discovery of these initiating events are crucial for gaining a better biological understanding of how cancer progresses. Conventional methods can only detect large DNA disruptions that may contain many genes, hindering precise identification of the genes responsible for cancer development. MSFHR funded William Lockwood for his early PhD research. He’s now continuing his comparison of DNA profiles of normal cells against cancerous cells. By labelling normal and tumour DNA with different dyes, he will be able to investigate the genetic changes that occur in progressing stages of cancer, in order to retrace the evolving patterns of gene disruption during cancer development. By distinguishing the initiating events, Lockwood’s research will shed light on the pathways driving the progression of cancer cells. This could lead to the identification of biomarkers to predict which early stage cancers are prone to develop into advanced tumours.