The role of Na+/H+ exchangers (NHEs) in pH regulation and brain function

The regulation of pH (a measure of acidity or alkalinity) is a highly sophisticated and tightly controlled process that is extremely important for proper brain function. Abnormal fluctuations in the pH of neurons (nerve cells) may be involved in the development of many neurological disorders such as epilepsy. Sodium-proton exchangers (NHEs) are membrane proteins that play an important role in maintaining and regulating cellular pH. Two forms of these proteins in humans, NHE1 and NHE5, are found at high levels in the brain. Graham Diering is investigating the exact function of NHE5, the only NHE that occurs almost exclusively and at high levels in the brain. NHE5 has been linked to familial paroxysmal kinesigenic dyskinesia (PKD), a neurological movement disorder. However, the precise involvement of the protein in PKD, and its role in proper brain function, are unknown. Diering is researching NHE5 in different brain structures, including mature and developing tissue, and examining the protein at the cellular level to determine where it may be active in nerve cells. An enhanced knowledge of the mechanisms in nerve cells that regulate pH could increase understanding of the factors that govern brain function, both in the normal and diseased state. As well, an analysis of specific molecules involved in this process could contribute to development of diagnostic and therapeutic strategies for treatment of neurological disorders.

Correlation Between Results from a New Magnetic Resonance Imaging Technique to Measure Myelin in the Spinal Cord and Somatosensory Evoked Potentials

Magnetic resonance imaging (MRI) is a powerful non-invasive imaging tool due to its ability to provide soft tissue contrast with high spatial resolution. Clinicians and researchers alike value MR images both for diagnosis and characterization of changes cause by disease. Recent advances have been made using MRI to image central nervous system white matter and investigate diseases that affect the white matter (such as Multiple Sclerosis), and damage to the spinal cord. The term “white matter” is derived from the white colour of nerve tracts. It appears white because of the layers of fat wrapped around each nerve fibre, called the “myelin sheath”. If the myelin sheath has been degraded or broken down, transmission of information along the fibre can be slowed down or lost completely. In the case of a narrowing of the spinal canal, the invertebral discs slip out of place and put pressure on the spinal cord, damaging the white matter tracts, resulting in symptoms like a feeling of numbness or tingling in the hands or feet. Somatosensory evoked potentials (SSEP) are a current clinical tool used to detect myelin degradation and nerve damage in the spinal cord. However, SSEP measurements are limited to only sensory pathway nerves, and cannot locate damage throughout the entire spinal cord. The UBC MRI Research Group has recently developed an MRI technique to measure myelin content in vivo, termed “myelin water imaging” (MWI), which can be applied throughout the brain and spinal cord. Erin MacMillan is applying the MWI technique to healthy adults and people suffering from narrowing of the cervical spinal canal. She hopes to find that MWI provides results consistent with SSEP measurements in sensory pathways, and identifies myelin degradation throughout the cervical spine. In addition, she will compare patient results from before and after surgery in the hopes of finding that the white matter has been repaired. If MWI proves to be an accurate measurement of myelin in the spinal cord, it could potentially be used to track myelin content during new spinal cord injury treatments aimed at degrading myelin in an effort to encourage nerve fibre repair.

Dynamic suppression of pathological brain oscillations in Parkinson's disease (PD) with virtual environments (VE)

Parkinson’s disease is a debilitating condition that affects millions of people worldwide, and is the second most prevalent neurodegenerative disorder in Canada. Typical symptoms include tremor, slowness of movement, difficulty in walking, and rigidity. Drug treatments and surgery are available to improve symptoms, but these forms of therapy are not always effective and can have serious side effects. As these options aren’t appropriate for all Parkinson’s patients, alternative, non-invasive treatments are needed. Parkinson’s symptoms are caused by a lack of the chemical messenger dopamine. Dopamine is normally released by neurons in the substantia nigra, allowing communication with the basal ganglia, an area of the brain that is responsible for the planning and smooth execution of movement. The lack of dopamine is believed to result in abnormal rhythms in the motor control areas of the brain, impeding movement. Recent studies have shown that appropriate stimuli can suppress the abnormal brain rhythms responsible for blocking movement in people with Parkinson’s and help improve the way people with the disease move and walk. Giorgia Tropini is researching the association between visual stimuli and ongoing brain rhythms. Using virtual environment technology and electroencephalogram (EEG) measurements, Giorgia is developing specific, precisely timed visual images to disrupt inappropriate brain rhythms. Ultimately, she aims to contribute to the development of a wearable, non-surgical, non-pharmacological device to treat Parkinson’s symptoms. Findings from her research could also be applied to other diseases that involve abnormal brain rhythms, such as epilepsy and depression.

Functional characterization of the chorea-acanthocytosis gene VPS13A in the yeast Saccharomyces cerevisiae

Many diseases such as cancer, atherosclerosis (narrowing and hardening of the arteries) and neurodegenerative disorders stem from problems with the uptake, transportation, storage and recycling of molecules. Proper sorting is necessary for normal cell function since many molecules are only required in specific areas or compartments of the cell. In the case of neurodegenerative disorders, defective protein sorting in nerve cells can lead to brain tissue deterioration. Disease caused by abnormal protein sorting can be studied in very simple organisms such as yeast, and the findings directly applied to human cells. Dr. Leslie Grad is researching a yeast protein, Vps13, which is very similar to a protein encoded by the human gene VPS13A. Defects in this gene can lead to chorea acanthocytosis, a neurodegenerative disorder associated with abnormal red blood cells, epilepsy, and muscle and nerve cell degradation leading to premature death. The findings could provide insight into the complicated mechanisms that regulate sorting of molecules inside cells and explain the molecular function of Vps13. Ultimately, Dr. Grad hopes to apply his findings to human cells and contribute to the development of therapies for neurological disorders caused by abnormal protein sorting.

Mechanical stress: an unexplored factor in regulation of cell signaling in DCIS and early breast cancer progression

Breast cancer is the second most common cause of cancer-related deaths among women in Canada. Deaths caused by invasive breast cancer that metastasizes (spreads to other parts of the body) are mostly preceded by a pre-invasive stage of the disease called ductal carcinoma in-situ (DCIS). This early stage is the ideal target in prevention of invasive breast cancer. Research has confirmed that features of the molecular activity of normal wound healing may play an important role in the spread of cancer from one area of the body to another. As cancer develops within any organ there is disruption of normal tissue. This disruption is like a wound and the response is like a scar. This process results in new mechanical forces within the tissue that act like a stress on tumor cells and have the potential to strongly influence a large number of cellular processes associated with tumor growth and invasion. Dr. Jiaxu Wang is researching the role of mechanical stress on cancer cells. He is investigating which genes are altered by mechanical stress in breast cancer cells. Wang is also identifying genes that are specifically altered by mechanical stress but not by other forms of stress that are known to exist in cancer tissues, such as lack of oxygen, to determine if these genes can be used to measure mechanical stress in DCIS lesions. The research will contribute to a better understanding of the specific role of mechanical stress in breast cancer progression. Wang’s ultimate goal is to develop markers that can predict or provide targets for therapy to improve outcomes for women with pre-invasive and early breast cancer.

In Vivo Evaluation of the Potential Role of Anti-Inflammatory Factors Involved in the Survival and Mechanism of Action of hRPE-Cell Implants for Parkinson's Disease

Parkinson’s disease is a neurodegenerative disorder that causes tremors, muscular rigidity, slowness of movement and postural instability. Affecting up to three per cent of the elderly population, Parkinson’s is characterized by depletion of the neurotransmitter dopamine and chronic inflammation in the substantia nigra region of the brain. While various pharmacological treatments alleviate symptoms of the disease, these medications eventually lose effectiveness and cause debilitating side effects. Cell-based transplantation therapies are being studied as alternative treatment options for Parkinson’s disease, but the routine use of these therapies has been delayed by mixed clinical results, safety and logistical concerns, and ethical issues. Recently, human retinal pigment epithelial (hRPE) cells have been proposed as a tissue transplant alternative for Parkinson’s disease and are currently being used in Phase II clinical trials. Found in the inner retina, hRPE cells are easily grown in culture so that a single donor can provide sufficient tissue for multiple recipients. Several studies have shown sustained reversal of Parkinsonian symptoms after hRPE implants with minimal side effects. Especially interesting is early evidence suggesting that transplanted cells may have the potential for long-term survival without requiring immunosuppressive drugs. However, little is known about the mechanisms of action of hRPE cells. Joseph Flores is researching the survival of implanted hRPE cells and the ability of implanted hRPE cells to replace depleted dopamine and induce a long-term anti-inflammatory response. A better understanding of hRPE-cell implants may lead to its routine use as a therapeutic alternative for Parkinson’s disease and improved outcomes for patients.

Spiritual Coping in Portuguese Immigrants to British Columbia

Numerous studies on the relationship between spirituality and mental and physical health have demonstrated that spiritual coping is an effective way of dealing with stress. Most research in this area has been conducted with members of ethnic and religious majorities. But little is known about how ethnic and religious minorities employ faith in coping with stress. Derrick Klaassen is examining the spiritual coping practices of Portuguese immigrants to British Columbia. Susan James and her colleagues at the University of British Columbia demonstrated that many of these immigrants suffer from a culture specific disorder termed agonias, translated as “”the agonies””. North American health care providers have generally misdiagnosed this problem as indigestion rather than anxiety or stress, and as a result the treatments have remained ineffective. Klassen has two goals for his research. The first is to add to the understanding of effective intervention for agonias by exploring the various healing systems that Portuguese immigrants employ (e.g. mental/health systems, spiritual, community, and cultural resources). The second goal is to examine the ways in which Portuguese immigrants use spiritual strategies to cope with agonias. Klaassen’s research involves conducting focus groups and revising an existing assessment tool for this community. The resulting questionnaire will serve both practitioners and scholars in their investigations of the role of spirituality in coping with stress in Portuguese immigrants. This project is part of a multi-stage program of research that will formulate a culturally sensitive treatment manual for health providers.

The role of the intestinal microbiota in host response to enteric pathogens

Many microorganisms reside in our bodies as part of normal living. For example, bacteria in the gastrointestinal system outnumber our own cells and form a stable connection with the body that persists for life. These resident bacteria are needed for parts of the digestive tract to develop and function properly. In addition, beneficial bacteria attach to the walls of the intestinal tract, preventing harmful bacteria from occupying these surfaces, and protect us from infectious diseases as a result. A lot of research has focused on disease-causing bacteria like E. coli and Salmonella, which are among the leading causes of gastrointestinal illness and death worldwide. Yet little is known about the role of beneficial bacteria in battling these microbes, which is the focus of Inna Sekirov’s research. She is examining what role resident bacteria play during the response of the intestinal immune system to infection and how these bacteria respond to antibiotics used to treat gastrointestinal illnesses. Findings from her research will help to establish whether drugs are likely to have a positive or adverse impact on a patient’s beneficial bacteria, and could also help inform new therapies or dietary regimes that complement or strengthen the ability of these bacteria to help the body fight infection.

Defining the structural basis of surface antigen glycoprotein mediated virulence in Toxoplasma gondii

Toxoplasmosis is a serious human pathogen carried by about one-third of the population. People develop toxoplasmosis either after ingesting undercooked meat that contains T. gondii cysts, or by coming into contact with cat feces from an infected animal. Once infected, healthy adults initially show a range of temporary flu-like symptoms; however, while these symptoms pass, the parasite Toxoplasma gondii remains in the body for life, with limited drug treatment available. Infection during pregnancy can cause miscarriage, neonatal death and a variety of fetal abnormalities, including developmental delays. It is also harmful to those whose immune systems are compromised, such as those with HIV/AIDS, cancer or who have had an organ transplant. Very little is known about how T. gondii causes disease. Dr. Martin Boulanger is studying the structure of host-pathogen interactions to determine the activities that allow T. gondii to attach to and invade human cells. With this information, treatments can be developed to prevent or manage Toxoplasmosis. This work will also apply to better understanding of other parasite-caused disease such as malaria and cryptosporidiosis.

Patterning and Organogenesis of the Mammalian Embryo

The development of a single cell to a multi-cellular organism, with each tissue and organ having a distinct architecture and function, is truly remarkable. Cells must co-operate and communicate with one another so they divide, migrate, form connections, change their identity, and die in co-ordinated patterns. These processes are complex, thus little is known about developing embryos and the genes that regulate their development. As an MSFHR-funded scholar, Dr. Pamela Hoodless examined how cells communicate with one another during embryonic development. This work continues, with a focus on two areas: the gut and heart. Congenital heart defects occur in about one per cent of births, making it a most common form of birth defect. With genomic technology, Dr. Hoodless can look closely at the genes involved in forming the valves and septa in the heart. She has identified two genes that control the activity of other genes, known as transcription factors, and is studying the functions of these genes in valve formation. Dr. Hoodless is also working to understand how the first stem cells of the gut are formed, and how these cells change to become other organs (liver, pancreas, stomach, etc). Identified for further study are three genes that are expressed (turned on) in these tissues, but not in the development of other body tissues. Understanding how gene regulation controls the development of the heart and gut in the embryo has far reaching implications for medical therapies, ranging from refining the repair of congenital defects to promising technologies such as stem cell therapies and tissue engineering.