Structural characterization of Propionibacterium acnes virulence factors

Acne is the most common skin disorder worldwide, affecting approximately 80 per cent of individuals at some point in their lives. How the skin develops this inflammatory condition is not entirely understood, nor is there a cure for severe, persistent cases of acne that often result in permanent scarring. Antibiotics are often prescribed as a first-line treatment, but the most effective antibiotic (Accutane) is known to have serious side effects, including birth defects and depression. In addition, antibiotic resistance is a growing problem. Propionibacterium acnes is present on most people’s skin and is the principal microorganism associated with acne. It can behave as an opportunistic pathogen under certain circumstances, expressing genes that lead to symptoms of acne. The genome of the bacterium has been sequenced and research has shown several genes that can generate enzymes for degrading skin, and proteins that may activate the immune system, leading to the initiation of acne, its development into inflammatory lesions and scarring. Angel Yu is focusing on O-sialoglycoprotein endopeptidase, a skin tissue-degrading enzyme. In order to understand how this protease works and how it recognizes its protein targets, she is growing crystals of the enzyme and using X-ray crystallography to study its structure at the atomic level. She will conduct studies that confirm the enzyme’s biological function and identify associated amino acid residues. Ultimately, Yu hopes her findings will provide insight into the molecular mechanism of this inflammatory skin disorder and identify new leads for the treatment of acne.

Structural and kinetic studies into eukaryotic sialyltransferases

The outer surfaces of mammalian cells are covered with a dense and complex array of sugar molecules. These sugars are important in many essential biological processes such as cell recognition, communication, neuron growth and immune defence. However, they are also used as attachment sites by a diverse range of disease-causing microbes and their toxins, and have been implicated in tumour cell metastasis. Many of these sugar-containing structures contain an essential sugar, sialic acid. The enzymes that transfer sialic acid onto these sugar structures are known as sialyltransferases. These enzymes are able to recognize numerous different types of sugar configurations. In fact, the human genome encodes at least 20 distinct sialyltransferases. Despite the importance of these enzymes, researchers know little about their molecular structure, their mechanisms, how they recognize their targets or how they are regulated. Dr. Francesco Rao is investigating the structure and mechanism of a mammalian sialyltransferase. This will give, for the first time, insight into how such enzymes work at the molecular level. This information could also be used to determine ways these enzymes could be therapeutically inhibited to combat infection or cancer metastasis.

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.

Presynaptic voltage-gated calcium channels: binding and regulation by SNARE proteins

Electrical signals are the fastest signals in our bodies. These signals are mediated by ion channels, specialized proteins that allow particular charged ions to pass through cell membranes. One class of ion channels, known as voltage-gated calcium channels, is of particular importance. They allow calcium ions to pass through the cell membrane when an appropriate electrical signal is present. In doing so, these channels play crucial roles in regulating heartbeats, in muscle contraction and in the release of hormones and neurotransmitters. The role of calcium channels in human health is significant. Mutations in the channels cause severe genetic diseases, and many drugs that are currently used to treat cardiovascular diseases, epilepsy and chronic pain target calcium channels to limit their dysfunction. Efforts to develop new drugs are hampered by the limits of what is known about the channels, particularly about their atomic structure. Dr. Filip Van Petegram is working to shed new light on the intricate workings of calcium channels that are expressed in the heart, in the brain, and in skeletal muscle. Van Petegram uses cutting edge technologies to gain a precise understanding of calcium channels. X-ray crystallography determines a protein’s atomic structure, producing high resolution structural images that serve as excellent templates for the design of new drugs, and provide valuable information about how the channels work. Electrophysiology measures the tiny electric currents that are generated when calcium ions pass through the channels. This work will contribute to novel treatment strategies for targeting calcium channels.

Video games can be good for you: an investigation of why games can be good and how to enhance their health benefits

In addition to video games being an enjoyable pastime for many people, research is increasingly indicating the beneficial effects of video game use on various cognitive abilities. Studies have demonstrated that in comparison to people who don’t play video games, “gamers” are typically better at focusing their attention and multi-tasking, and they demonstrate superior spatial processing and faster reaction times. A growing amount of anecdotal evidence suggests that video games could have health benefits, such as the use of video games as rehabilitation for stroke patients, or for improving the speed and accuracy of surgeons performing laparoscopic surgery. Although previous work has identified that video game use can lead to enhancements in attentional processing in the brain, research to date has been limited to studying how the brain orients its attention to tasks without considering the role of eye movements in this process. Joseph Chisholm is using video games to investigate the attentional differences between game players and non-game players. He is focusing on the use of “distractors” – objects or events that attempt to capture an individual’s attention and distract from the task at hand. He will compare the ability of game players and non-game players to control what they pay attention to by measuring reaction times and eye movements. In identifying the mechanisms underlying how gaming enhances attentional control, this research could yield potentially novel and specialized treatment options for individuals with deficiencies in attentional processing, such as stroke patients.

Engineering of carbohydrate processing enzymes for generation of therapeutic glycoproteins with increased serum halflife

Biopharmaceuticals are molecules produced using biotechnology, rather than chemistry, for therapeutic purposes. Biotechnology uses microorganisms (such as bacteria or yeasts) or biological substances (such as enzymes) to manufacture pharmaceutical compounds. Many biopharmaceuticals are very large proteins, which show considerable promise in the treatment of a wide range of diseases. Unfortunately, owing to the complex mechanisms that the body requires to regulate its own proteins in the bloodstream, foreign proteins in the form of medicines are typically rapidly destroyed or removed from the circulation by the body. Sugars found on the surface of mammalian proteins protect provide protection from destruction by circulating protein-degrading enzymes. They also provide a signal when it is time for a protein to be removed from the blood. Dr. Jamie Rich is investigating whether adding specific sugars to protein drugs could help them last longer in the bloodstream and be more effective. He is working to develop an enzyme that can “build” a particular type of sulphur-containing sugar onto the surface of the protein drug. This promises to protect the protein from degradation, prevent the exposure of sugar-based clearance signals, and allow the protein to function normally as an effective long-lasting drug. Creating longer-lasting drugs would reduce the required amount and frequency of dosages, resulting in reduced drug costs. If successful, this approach could be applied to a wide range of proteins that are currently used as drugs or are in the drug development stage.

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.

Individual differences in stress coping and predisposition to disease.

Glucocorticoids are hormones that the body releases into the bloodstream in response to stress, protecting our bodies in the short term against the damaging effects of stress. Chronic oversecretion of these stress hormones can lead to various mental health disorders such as anxiety and depression. Humans show extreme differences in how they adapt or succumb to the pathological effects of stress. Sex steroids play a critical role in individual and gender-based differences in stress-induced pathology, but the basis for this in the central nervous system is not understood. Independent studies in rodents and humans show that testosterone can regulate the magnitude of the glucocorticoid and behavioural responses to stress. With this data, Dr. Victor Viau is working to determine how testosterone operates on stress-related pathways in the brain, from a physiological and chemical perspective. He is investigating how early-life exposure to testosterone determines the brain’s response to stress during adulthood, and providing insights about the underlying factors that allow the individual to manage stress in different ways. Viau’s research program is unique as it aims to determine how, where, and when stress and testosterone interact in the nervous system and at the hormonal and behavioural levels. The research will ultimately provide a fundamental framework for understanding why some individuals succumb to the psychopathological effects of stress and others persevere in the face of it.

Spatial modulation of vestibular reflexes by the cerebellum characterized in healthy volunteers and spinocerebellar ataxia patients

While maintaining balance appears effortless and relatively simple, it depends on a complex integration of sensory and motor signals that originate from a variety of sources in the body. When you turn your head, even though the vestibular organs of the inner ear change their orientation relative to the body, they still provide information which can be used to aid balance. This response relies on information received from vestibular organs (which measure linear and angular acceleration of the head) and sensory information from the neck (which conveys the head’s position). These two signals are then integrated to provide contextually specific directional information to the brain. As such, patients with damage to their vestibular organs tend to be posturally unstable. The cerebellum has emerged as a potential contributor to the convergence and interpretation of vestibular and somatosensory information in the brain. Patients with cerebellar dysfunction often exhibit similar abnormal balance behaviour to those with vestibular damage. Christopher Dakin is investigating the cerebellum’s role in the vestibular systems influence on balance. He is comparing postural responses associated with vestibular activation among two groups: healthy people, whose cerebellar function is temporarily inhibited by a technique called Transcranial magnetic stimulation; and individuals with spinocerebellar ataxia, a neurological disease marked by atrophy (wasting) of the cerebellum. By increasing our understanding of the human nervous system as it relates to cerebellar processing of vestibular information, Dakin’s research will contribute to more accurate balance disorder diagnoses and treatments. Ultimately, his work could lead to improved therapeutic and rehabilitative techniques directed towards patients with vestibulo-cerebellar dysfunction.

Chondrogenic gene expression in repetitive-use tendon injury

Tendon has to withstand high tensile forces to do its job properly, acting as a mechanical link between muscle and bone to allow joint movement. Repetitive-use tendon injury, known as tendinopathy, affects workers in many key Canadian industries, as well as professional and recreational athletes. Standard anti-inflammatory treatments are unsuccessful in treating tendinopathy, and new treatments are needed to relieve the burden of chronic tendon pain. Normal tendon is composed of rope-like molecules (type I collagen). In contrast, in tendinopathy the collagen can become spongey – like in cartilage (type II collagen). The tendon becomes less able to resist tensile forces, and more prone to microtearing, pain and rupture. Dr. Alexander Scott is investigating what triggers tendon cells to switch their metabolism to produce less type I collagen and more type II collagen. Scott is conducting a combination of molecular and biomechanical studies both with tendon fibroblasts and with tendon progenitor cells. Scott is also studying transcriptional regulation during tendon injury using a transgenic reporter system, and in patients with tendinopathy. Scott’s research is aimed at developing evidence-based treatments for chronically painful tendons. Ultimately, this could open up new therapeutic options for restoring tendon health.