Because many forms of leukemia originate in blood stem cells, uncovering the changes that occur in these cells is crucial to understanding how these diseases develop and progress. Dr. Xiaoyan Jiang is studying Ahi-1, a newly-discovered oncogene (cancer causing gene) that is involved in murine leukemia development (leukemia in mice) and shows abnormal expression in human leukemic cells, including leukemic stem cells from patients with chronic myeloid leukemia and Sezary cancer cells from patients with cutaneous T-cell lymphoma. Her research team recently found that over-expression of Ahi-1 gene alone can cause leukemia in mouse models and suppression of Ahi-1 gene can normalize its transforming activity in human leukemia cells, a strong indicator that Ahi-1 is likely to be an important new oncogene involved in the development of leukemia in humans. Dr. Jiang’s research will explore the normal function(s) of Ahi-1 in the development of blood cells, and how this is altered when cells become leukemic. This research will also begin to identify new intracellular molecules that interact with Ahi-1 and the cellular and molecular pathways through which these interactions occur. Understanding how and by which pathways Ahi-1 contributes to the development of leukemia may provide important new molecular targets for the development of targeted cancer treatment that will be more effective and have fewer side effects than currently used chemotherapy.
Research Pillar: Biomedical
Creation and function of neighborhoods in eukaryotic chromosomes: regulation by SWR1-Com, a desposition complex for histone variant H2A.Z
Chromatin is the complex of DNA and protein material that make up chromosomes, home to the genetic code. The basic unit of chromatin is the nucleosome, a fundamental building block consisting of DNA wrapped around an octamer of histone proteins. A large number of proteins involved in cancer development and the genetic susceptibility to devastating diseases such as Ataxia Telangiectasia (a progressive immunological and neurological disorder) act through modification of chromatin structures and interfere with normal chromatin function. Differences in chromatin structures between adjacent regions specify the properties of larger macrodomains called neighbourhoods. The shape and structure of these neighbourhoods influence chromosome behavior, while complex regulatory mechanisms that ultimately involve chromatin ensure that each cell expresses only the appropriate genes, duplicates its genome with high fidelity, divides only when required, all while combating constant assaults on its DNA. Failure in any of the mechanisms regulating these events can lead to disease. These chromatin structures themselves can also be inherited, creating an additional complex set of influences that are crucial for the identity and activity of the cell. The molecular biology of chromatin structures and their role in chromosome biology and genome function in health and disease is the focus of Michael Kobor’s research. Specifically, he is studying a unique chromosomal neighbourhood containing a specialized histone variant known as H2A.Z, which is deposited into chromatin by a large protein complex. Using innovative genome-wide approaches, Dr. Kobor’s team aims to uncover the rules and principles of histone variant function.
Caenorhabditis elegans dog-1 gene mechanism in genome stability
Genes that contribute to normal cell reproduction, growth and DNA repair are essential for healthy cell function in all organisms. The dog-1 gene plays a role in maintaining the stability of the genome of Caenorhabditis elegans, a tiny worm frequently studied by researchers because it has many molecular characteristics that are central to human biology. However, little is known about how the dog-1 gene functions to maintain genome stability. Jillian Youds is studying how this gene functions in the cell to gain a better understanding of how it contributes to DNA sequence stability. Given that mutations in the genes required for stability are often underlying causes of disease, this research could provide further understanding of the development of cancer.
Functional characterization of Bardet-Biedl proteins
Bardet-Biedl Syndrome (BBS) is a complex genetic disease that affects many different body parts, including the eyes, kidney and heart. Symptoms include blindness, obesity, diabetes, kidney dysfunction, congenital heart defects and extra fingers or toes. At least eight genes (BBS1 to BBS8) are linked to the syndrome. Recent studies suggest that defective cilia (short, hair-like projections that protrude from the cell surface and help clean out airways) may be the primary cause of the syndrome. Junchul Kim is investigating whether this defect causes Bardet-Biedl Syndrome. He is studying the role of proteins encoded by BBS genes to see if mutations in these genes affect different body parts during development. This research could provide insights into how the syndrome develops and potentially lead to new treatments for many common disorders, such as diabetes and obesity.
The role of a novel gene involved in autophagic programmed cell death
All multi-cellular organisms begin as a single cell that multiplies and develops into a fully formed adult. While millions of cells are produced during development, the process of programmed cell death (apoptosis) removes obsolete cells. Errors in this process can cause neurodegenerative disorders and cancers. Suganthi Chittaranjan aims to identify the genes that control cell death. Using powerful tools available at Canada’s Michael Smith Genome Sciences Centre, Suganthi has identified 500 genes that are activated before cells die. One gene in particular may play a role in both programmed cell death and the immune system’s defensive response. If the research succeeds in identifying a common gene that controls both processes, the gene could be used as a target in developing therapy for controlling cancer and improving the immune system of cancer patients.
The role of the PI3K pathway in embryonic stem cell proliferation and differentiation
Embryonic stem (ES) cells have the ability to differentiate into any cell type, such as skin, muscle or nerve cells. Differentiated ES cells potentially could be used to replace damaged tissues. However, undifferentiated EC cells form benign tumours following transplantation, thus ES cells must first properly differentiate into the desired cell type. Frann Antignano is investigating what causes ES cells to either self-renew or differentiate. The long version of a protein called SHIP plays a role in differentiation, while a shorter version called sSHIP is found in undifferentiated cells. Frann is examining the role of sSHIP in ES cell renewal by reducing the protein’s levels to see if that leads to increased self-renewal. Results from the research could lead to therapies for controlling ES cell differentiation to treat a variety of conditions, including Parkinson’s disease.
Acid extrusion from rat hippocampal neurons; the potential role of a voltage-gated proton conductance
Intracellular pH, the amount of acid inside neurons (brain cells) changes during normal cellular activity and with conditions such as stroke. Left unregulated, these changes can alter brain cell function and contribute to their death following a stroke. Consequently, cells have developed mechanisms to maintain their intracellular pH within normal limits. The hippocampus, a part of the brain associated with learning and memory, contains some cells that are very susceptible and some that are very resistant to stroke-related cell death. Research has identified three mechanisms that regulate pH in hippocampal brain cells, but recent evidence suggests that these mechanisms are inhibited during a stroke. May Cheng is investigating whether there is a fourth mechanism, a voltage-gated proton conductance, that regulates pH by discharging detrimental acid from these cells. Identifying this additional mechanism could lead to new strategies to prevent or limit brain cell death following a stroke.
Host resistance and Salmonella Typhimurium Gastroenteritis
Salmonella species cause a variety of diseases, including diarrheal and systemic illness, signicificant causes of morbidity and mortality in the developing and developed world. To cause disease in healthy people, bacteria such as Salmonella typhimurium must first breach physical barriers, such as the mucous membrane lining internal organs, and then successfully avoid detection and destruction by the immune system. Gastroenteritis (inflammation of the stomach and intestine) in healthy humans and systemic illness in people with compromised immune systems result from the successful evasion of Salmonella typhimurium. Resistance to infection depends on a wide array of immune factors. Bryan Coburn is researching the role of host resistance factors and also the response of bacteria to these defenses in Salmonella-induced gastroenteritis. The research will potentially provide important insights about the mechanisms that influence susceptibility or resistance to Salmonella-induced gastroenteritis.
Identification of potential molecular markers and therapeutic targets involved in the progression of mantle cell lymphoma
Mantle cell lymphoma (MCL) is an aggressive cancer of the lymphatic system that is incurable with chemotherapy or radiation. MCL has a survival rate of approximately three years, with no long-term survivors. Ronald deLeeuw is studying the biology of this disease to learn more about how it progresses. He is focusing on secondary genetic alterations concurrent to a characteristic feature of MCL: the switching of a genetic segment from one chromosome to another (translocation), which results in uncontrolled growth of lymphatic cells and an unregulated growth signal. Using new technology that reveals previously undetectable genetic changes, Ronald is compiling a comprehensive list of secondary genetic alterations that could contribute to progression of MCL. The research could provide insights about potential targets in treatment of MCL.
Assembly of Postsynaptic Protein Complexes in Hippocampal Neurons
Synapses, the connections that enable brain cells to communicate with each other, are fundamental to normal brain function. Studies suggest synapses form and mature quickly—in a few hours—but the molecular interactions that trigger this process in the central nervous system are unclear. Kimberly Gerrow is researching the molecular stages of synapse development in the hippocampus, a part of the brain involved in cognitive functions such as learning and memory. She is investigating the role of PSD-95 protein (postsynaptic density protein), in assembling molecules crucial for creating synapses. This could lead to improved understanding and treatment of neurological disorders that result from interruptions or abnormalities in synaptic development. The findings could also offer insights into ways of re-establishing functional brain connections that have been damaged by conditions such as stroke, Parkinson’s and Alzheimer’s disease.