Infectious diseases are responsible for up to a third of deaths reported worldwide. A large percentage of these deaths are directly related to bacterial infections. Bacterium that cause infections, such as E.coli, thrive because of their ability to rapidly adapt to changes in their environment. The ability to rapidly adapt stems from tight control over the expression levels of proteins within the bacterium. The messenger RNA (mRNA) is a template that codes for proteins ready to be expressed within the cell. The instability of mRNA allows E.coli bacteria to quickly change the expression levels of proteins within the cell in order to adapt and survive when it invades a host cell. E.coli employs a protein complex called the RNA degradasome to degrade mRNA for this purpose. Using X-ray crystallography (a technique for determining the 3D structures of molecules), Dr. Trevor Moraes is researching how the RNA degradasome functions. This analysis of key processes involved with disease-causing bacteria could contribute to the development of new antibiotics to fight bacterial infections.
Research Location: University of British Columbia - Point Grey
Proteasomal degradation of BACE in the pathogenesis of Alzheimer's disease
Alzheimer’s disease is the most common neurodegenerative disorder causing dementia in older people. With Alzheimer’s, brain cells shrink or disappear and are replaced by irregularly shaped spots or plaques. The amyloid beta (A-beta) protein is a central component of these plaques. A-beta is a normal part of brain cells, but is toxic in high concentrations. Dr. Yigang Tong is studying why there is an increase in A-beta proteins with some older people. He is focusing on the role of the BACE enzyme that produces this protein because he believes degradation of this enzyme is impaired, allowing the amount of A-beta to increase in brain cells. Identifying the steps involved in the degradation of the BACE enzyme could help explain how Alzheimer’s disease develops and potentially lead to new drugs to treat the condition.
Probing the preparation and preprogramming of voluntary movements using startle in healthy humans and clinical populations
Every day people are required to make quick, voluntary responses to environmental signals, such as sound. The higher brain (cerebral cortex) has long been thought to control these movements by receiving and analyzing sensory information and coordinating responses. But Anthony Carlsen’s research has shown reactive movements can be stimulated more quickly with a loud, startling sound at 124 decibels. The research suggests it may be possible to pre-program these quicker responses and store them in the midbrain, the area that controls auditory and visual reflexes. Anthony is using Functional Magnetic Resonance Imaging (fMRI) to determine if there is brain activity with pre-programmed responses in the midbrain. He is also testing whether the startling sound triggers a midbrain response in people with Parkinson’s disease and those who become deaf following a stroke. Results from the study could provide insights about human motor control, the source of movement deficiencies caused by Parkinson’s, and potential treatments for people with Parkinson’s and cerebral deafness.
Structural characterization and inhibitor design of sialyltransfersases involved in lipooligosaccharide biosynthesis of Gram-negative pathogens
Bacterial resistance to antibiotics has become a major challenge in drug development. It is thus necessary to develop novel antimicrobial therapies to combat bacterial infection. Such development would require a thorough understanding of the mechanisms bacteria employ to cause disease. Campylobacter bacteria is the most commonly reported foodborne pathogen that cause acute gastroenteritis (inflammation of the stomach and intestines) and diarrheal illness in developed countries. Almost 99% of the reported cases are caused by a specific strain, called C. jejuni. Sialic acid (sugar molecules) on the cell surface of C. jejuni mimics human gangliosides and thus camouflages the bacteria from the host immune system. Cecilia Chiu is investigating the three-dimensional molecular structure of sialyltranferases, the class of enzymes responsible for the transfer of sialic acids onto the surface of Campylobacter. Cecilia aims to understand the mechanism of these enzymes and to develop molecules that inhibit the enzymes from sialylating the bacterial cell surface. This research could ultimately lead to the development of new therapeutic inhibitors against this common human pathogen.
The development and function of self-specific CD8+ CD44high T cells
About 38 percent of women and 41 percent of men will develop cancer during their lives. These staggering numbers highlight the need for new preventive measures and treatments for cancer. The human immune system is capable of eliminating pre-cancerous cells before they get a chance to grow. Salim Dhanji is researching how this process occurs. He is focusing on the development and function of a subset of T cells that control the immune system and fight infection. Salim aims to determine the conditions that maximize the ability of these cells to kill cancer cells. He ultimately wants to develop a strategy for using the body’s own immune system to fight cancer.
Functional modulation of N-methyl-D-aspartate receptors (NMDARs) by mutant huntingtin
Huntington’s disease (HD) is a hereditary, degenerative brain disorder that gradually diminishes movement and memory. HD has no cure and there are no treatments that prevent or slow the disease. Symptoms appear in middle age, with death usually occurring within 20 years as cells in specific parts of the brain slowly die or stop functioning properly. Mannie Fan is investigating the function of the huntingtin protein that causes HD, and also the molecular mechanisms that underlie development of the disease. Studies show that the death of brain cells associated with HD may result from too much activity in molecules called NMDA receptors, which normally facilitate brain cell communication. Mannie is investigating the underlying mechanisms that contribute to this increased activity. The research could help explain why people with the huntingtin protein develop HD and possibly lead to novel strategies for treating or preventing the disease.
Relevance of aberrant activity in the temporal lobes during development to cognitive and behavioral impairment: a potential animal model of schizophrenia
People with schizophrenia experience symptoms such as delusions, hallucinations and disturbances in thinking, and often become fearful and withdrawn. Determining the cause of schizophrenia is difficult due to the heterogeneous nature and complexity of the disorder. Current theories suggest abnormal development in brain regions that regulate movement, emotion, speech, behaviour, learning and memory may cause schizophrenia. John Howland is studying whether altered interactions involving dopamine and glutamate — chemicals that carry messages between brain cells — can result in behaviour that is consistent with schizophrenia. This research could provide support for theories that developmental abnormalities cause schizophrenia.
Involvement of postsynaptic density proteins in synaptic specificity and spine formation
Neurons (brain cells) communicate with each other through a highly complex network of connections called synapses. Different types of synapses perform different roles. Abnormalities in these connections may be linked to psychiatric disorders including autism and schizophrenia. Joshua Levinson is investigating how neurons establish these contacts so consistently that virtually no errors occur despite their diversity. He is looking specifically at levels of particular proteins at the site of contact and how these levels affect the type of connection formed between neurons. He is also studying how these connections stabilize, which is critical for connections to form properly, and if proteins play a role in the stabilization process. The research could lead to a clearer understanding of the neurological abnormalities that underlie psychiatric diseases such as autism and schizophrenia, and contribute to more effective treatments.
The role of antigen presenting cells in viral induced autoimmune diabetes
An autoimmune response occurs when the body’s immune system mounts an attack on its own organs or tissues. Type 1 diabetes, for example, results when immune cells destroy insulin-producing cells in the pancreas. Although genetic predisposition is a major factor, seemingly benign viral infections also may play a role in this disease. However, the mechanisms by which viral infections cause autoimmune disease remain unclear. Martin Richer is researching how viruses cause autoimmune type 1 diabetes. He is investigating the mechanisms by which the immune system is sensitized by exposure to a virus and mounts an attack on normal cells. Martin is also studying how this activity influences the development and progression of disease, and how the process can be regulated. The findings could improve understanding of how viral infections lead to autoimmune responses and diseases such as type 1 diabetes.
Nrf2-mediated activation of Phase II detoxification genes as a novel neuroprotective strategy for stroke
Stroke is the fourth leading cause of death in Canada. A number of factors contribute to nerve cell death during a stroke. One major cause is the accumulation of free radicals (oxygen molecules that take electrons from healthy cells in the process known as oxidation), which causes cellular damage. Compared to other brain cells, nerve cells are particularly susceptible to damage by free radicals. Damage to nerve tissues worsens over the hours or days following a stroke due to an imbalance between free radicals and the antioxidants that normally protect cells. Andy Shih is researching ways to increase antioxidant levels to maintain balance and prevent cellular damage during stroke. Andy is specifically examining the ability of the Nrf2 protein to launch the cell’s antioxidant defenses, remove free radicals and repair damage. This research could confirm if Nrf2 can promote neuronal survival after stroke, hopefully improving functional recovery. Interestingly, a number of molecules that can activate Nrf2 are found in cruciferous vegetables, such as broccoli. Diet-based therapies that favour Nrf2 activation could be effective and practical therapeutic approaches.