Microsporidia are a group of parasites that infect animals and immunocompromised humans. In infected individuals, they cause severe diseases, like encephalitis (inflammation of the brain) and gastroenteritis (inflammation of the stomach). As organisms that are dependent upon their host for survival, some of the microsporidia’s organelles (internal structures) and metabolic functions are missing or deficient in comparison to other single-celled organisms. One example is the mitochondrion, an organelle that normally contains many enzymes important for cell metabolism, including those responsible for the conversion of sugar to usable energy. A highly reduced relic of the mitochondrion was recently discovered in microsporidia. The role and metabolic function of this deficient organelle remain unclear. Dr. Lena Burri’s research project is to identify and characterize proteins that are imported into the mitochondrion, how these proteins are directed to their final destination and in which metabolic pathway they are involved. Understanding the function of the relic mitochondria in microsporidia may provide ways to combat these organisms, as mitochondrial functions are important potential drug targets.
Research Pillar: Biomedical
Identification and characterization of mycobacterial secreted protein that interacts with the actin-binding protein coronin-1/TACO in human macrophages
The recent increase in cases of tuberculosis, mainly due to an association with human immunodeficiency virus, poor living conditions, and the emergence of drug-resistant strains, has been described as a “”global emergency”” by the World Health Organization. New therapeutic strategies are urgently needed and this requires a better understanding of the interaction of the causal agent, Mycobacterium tuberculosis, with the host cells, which include macrophages. Macrophages possess a powerful intracellular killing mechanism and play an essential role in immunity, but they are also the principal targets for mycobacterium. Mycobacterium inhibits the intracellular killing as well as antigen presentation at the cell surface to stimulate adaptive immunity. Dr. Ala-Eddine Deghmane is studying the molecular mechanisms by which pathogenic mycobacteria interferes with macrophage functions. His research aims to advance understanding of the host cells’ failure in resisting to mycobacterial infection and may lead to preventive and therapeutic anti-TB strategies.
Activity of identified spinal interneurons during wakefulness and sleep
Although they severely affect the lives of millions of individuals, Restless Leg Syndrome (RLS) and rapid eye movement behavior disorder (RBD) are two sleep disorders that are not commonly diagnosed. Unlike more common conditions like sleepwalking, RLS and RBD movements occur during REM sleep or natural active sleep (AS), which are usually characterized by a state of atonia, or sleep paralysis. During AS, sensory transmissions to the brain are reduced; spinal inhibitory interneurons (neurons confined wholly within the spinal cord) are thought to underlie this reduction. However, virtually nothing is known on how these spinal interneurons are regulated. Dr. Yanshen Deng is investigating how the activity of certain spinal interneurons change as a consequence of alterations in behavioural state e.g. wakefulness vs. sleep. She is researching how these spinal interneurons are triggered to inhibit specific spinal sensory channels, and whether such interneurons are facilitated during AS. Yanshen’s research aims to advance basic sleep and spinal cord science and may help advancement of knowledge in sleep-related sensorimotor disorders such as RLS and RBD and pain following spinal cord injury.
Analysis of a role for Hippi / IFT57 in regulation of embryonic laterality and sonic hedgehog signalling
Research has shown that defects in cilia, small hair-like structures on the outside of cells, are the cause of many disorders including infertility, blindness, deafness, kidney defects and breathing difficulties. It has been shown that some of these defects arise when there are mutations in components of these cilia known as “”Intraflagellar Transport proteins”” (IFTs). These faults may render the cilia immobile, shorter than normal, or even completely absent and can lead to alterations in the normal layout of adult organs such as the heart, liver, and lungs. There are an increasing number of diseases linked with the IFT family of genes. Dr. Robin Dickinson is studying the role of one of them, known as Hippi / IFT57. Robin is investigating what these genes do when active, and examining the effects of their loss. Robin hopes that research into their function will lead to development of therapies for diseases caused by defects in cilia.
Identifying direct target genes of Notch signaling in endothelial cells during endothelial-to-mesenchymal transition
Congenital heart defects due to anomalies in heart development occur in one percent of newborns. A critical event during heart development is the transformation of a subset of cells that line the inside of the heart, called endocardial cells, into mesenchymal cells. This process, termed endothelial-to-mesenchymal transition (EMT), generates cells to form heart valves and walls that divides the adult heart into chambers and regulates blood flow. If EMT does not progress properly, normal heart development is disrupted, resulting in the most common type of congenital heart defects. Notch proteins (signaling molecules that trigger genes to activate) play an important role in EMT as the activation of Notch signaling induces the EMT process in endothelial cells. Dr. Yangxin Fu’s research goal is to identify the direct target genes of Notch signaling that are critical to EMT. Using cell culture and molecular biology tools, including a cutting-edge, high throughput technique, Yangxin is analyzing thousands of candidate genes and searching for Notch target genes critical for EMT and heart development. This study will help to understand the molecular mechanism underlying the role of Notch signaling in EMT and in the long term it may find potential target molecules to prevent and treat the heart defects caused by disruption of Notch signaling.
T Regulatory cells in toxoplasma pathogenesis
Toxoplasma gondii, commonly acquired by eating under-cooked meat, is a particularly successful pathogen that establishes life-long infections with its capacity to infect, replicate and persist chronically within host immune cells. Toxoplasma causes an acute, influenza-like disease that typically becomes a chronic infection. Immuno-suppressed individuals are at risk for developing chorioretinitis (inflammation of the choroid layer behind the retina), blindness and fatal encephalitis. An emerging concept in the immunology of infectious diseases is that persistent pathogens like Toxoplasma establish chronic infections by activating T regulatory cells (Tregs), which are thought to have the ability to selectively suppress immune responses. Dr. Andrew Hall is investigating the immunological basis of Toxoplasma persistence and how this pathogen evolves to promote Tregs. He aims to determine the molecular details governing Treg generation and function, and to establish their role as critical immune regulators of persistent infections. Andrew hopes that results from his research will help to develop novel methods of immunotherapy or vaccines designed to target the regulatory T-cell network in disease and to contribute significantly toward the development of cures.
A subunit-specific role for NMDA receptor antagonism in neonatal seizures: in vivo and in vitro characterization
Seizures are more common during an infant’s first month than at any other time during their development. They are caused by temporary abnormal electrical activity in the brain and can have long-lasting consequences such as memory impairments and an increased risk for epilepsy. Unfortunately, anticonvulsant treatments are ineffective for at least 35% of babies who have seizures as newborns. Currently, the mechanisms underlying the onset of these seizures are unclear. While research indicates that increased transmission of glutamate (a neurotransmitter) may result in seizures in the adult brain, there have been indications that seizures in newborns may be triggered by a reduction in glutamate transmission. These and other findings suggest that certain glutamate receptors may have different roles in causing seizures over the course of neurological development. Dr. John Howland is investigating the role of glutamatergic transmission levels and seizures during the neonatal period. He is analyzing two highly specific glutamate receptor antagonists (blockers) to determine the specific receptor subtypes involved in triggering seizures. Results from his research may have significant implications for the understanding of neonatal seizures and the development of novel drug targets for their prevention and treatment.
Synthesis of stably glycosylated therapeutic glycoproteins
The majority of therapeutic drugs now in use are “so-called” small molecules – compounds that exert their desirable effect by interrupting or otherwise interfering with an abnormal physiological process. More recently, a new class of protein-based drugs has been developed, including various growth factors and Epoetin. Most protein-based drugs have sugars attached to their surface that are known as glycoproteins. These sugars play a role in directing the drug to its site of action and maintaining the protein in the bloodstream. If enzymes in a patient’s body cut or cleave the sugar molecules from the protein, the drug is cleared from the body. If scientists could produce more stable forms of glycoproteins, the drugs would remain in the bloodstream, reducing and potentially eliminating the need and costs of frequent doses. Using newly developed methodologies created in the laboratory of his supervisor Dr. Stephen Withers, Dr. Young-Wan Kim is working to address this issue by engineering new enzymes that would attach sugars via a sulfur atom and allow, for the first time, the generation of stable versions of these therapeutic proteins.
Examining the effects of the intestinal bacterial community on enteropathogenic infection
All animals are colonized by a large number of non disease-causing microorganisms, referred to as the normal microbiota. Sites colonized by these microorganisms include the skin and the genital tracts, with the most heavily colonized site being the large intestine. The intestinal microbiota carries out important roles in a variety of areas, such as absorption of nutrients and prevention of infectious disease. Dr. Claudia Lupp is investigating the importance of the intestinal microbiota in diarrheal disease caused by enteropathogenic Escherichia coli (E. coli). Enteropathogenic E. coli include the human pathogens enterohemorrhagic and enteropathogenic E. coli (EHEC and EPEC), which cause significant illness and death around the world. She will use the closely related mouse pathogen Citrobacter rodentium as an experimental model to determine the effects of diarrheal disease on the normal microbiota and to investigate how the microbiota might be manipulated in order to prevent disease. Understanding the body’s innate defenses against infectious disease, including those provided by the normal microbiota, is important for health maintenance. This information ultimately may be used for strategies to prevent and to cure infectious disease by bolstering the body’s natural defenses.
Utilizing yeast and mammalian approaches to identify chromosome instabilities underlying colorectal cancer in humans
The molecular mechanisms that ensure proper chromosome segregation during the division of cells are of fundamental importance to maintaining the integrity of the genome (genomic stability). In humans, genomic instabilities arising from chromosome instabilities (CIN) or missegregation are known to be implicated in the development of certain types of cancer. Mutations in genes that cause genomic instability are now recognized as being important predisposing conditions that contribute to the initiation and progression of cancer. Using budding yeast as a model, Kirk McManus hopes to identify both the non-essential and essential genes of yeast regulating CIN for comparison with mammalian cells to determine any cross-species candidate genes that contribute to genome instability. A better understanding of the genetic basis of CIN in model organisms will provide candidate genes for those CIN genes mutated in cancer. The results of this research will be directly relevant to an understanding of cancer mechanisms, and may be useful in developing strategies for cancer therapy and for sub-classification of tumors based on their CIN mutational spectrum.