Research Location: University of British Columbia - Point Grey

There are a great number of genetic diseases that affect tooth number in humans. Ectodermal dysplasia (ED), for instance, is characterized by a reduction in the overall number of teeth (i.e., hypodontia). In contrast, people with cleidocranial dysplasia (CCD) may form dozens more teeth than normal. In both disorders, only the secondary generation of teeth (‘adult teeth’) is affected, while baby teeth are largely unaffected. Since conventional mammalian lab models, such as the rat and mouse, form only a single generation of teeth during their lives, they can tell us little about the molecular cues controlling tooth replacement. For this reason, Dr. Gregory Handrigan has turned to an unusual animal model: reptiles. Like humans, reptiles form multiple generations of teeth throughout their lives. As part of the first research to directly address the molecular control of generational tooth formation, Dr. Handrigan is identifying genes from reptiles such as the python and bearded dragon that underlie their ability to continually form new teeth. Given the overwhelming similarity in tooth development between reptiles and mammals, these genes are likely to be performing comparable roles in humans. Handrigan’s research could then generate important knowledge about the molecular control of tooth number in human development as well as for diseases like ED and CCD. Ultimately, his findings may provide a foundation for strategies to regenerate lost teeth in humans.

Influenza is a severe infection of the upper respiratory tract that occurs each year, affecting approximately 20 per cent of the world’s population. Although vaccination is the primary prevention strategy, a number of scenarios exist for which vaccination is insufficient and for which the development of new antiviral agents would be extremely important. Two classes of drugs are available for controlling the spread of influenza. Amatidines work by blocking the ion channel function of the viral M2 protein. However, these drugs are only effective against influenza A virus and have substantial side effects. The other class of therapeutics, sialidase inhibitors, includes enzyme inhibitors Relenza and Tamiflu. However, influenza viruses are developing resistance to both inhibitors. One solution to the problem of viruses becoming resistant is to use several drugs at once (a drug cocktail), making it more difficult for the virus to develop resistance to all of them. Another solution, which could be used in concert, is to design new inhibitors that are less likely to induce viruses to mutate and develop resistance. This is the goal of Dr. Jin Hyo Kim’s research.

One way of classifying bacteria is by their colour after applying a chemical stain (called the Gram stain). Some bacteria stain blue (Gram-positive), while others stain pink (Gram-negative). Gram-positive and Gram-negative bacteria produce different kinds of infections. Worldwide, more than half of infections treated in hospital involve Gram-positive bacteria. These include Staph infections caused by Gram-positive Staphylococcus aureus bacteria, as well as Strep throat and toxic shock syndrome caused by Streptococcus bacteria. Many Gram-positive bacteria, such as methicillin-resistant Staphylococcus aureus (MRSA), are becoming resistant to antibiotics. The cell wall of all Gram-positive bacteria contains about 50 percent of teichoic acids, a diverse group of polymers (long-chain molecules). Dr. Leo Lin is investigating whether two common teichoic acids help these bacteria adhere to host cells in humans or even to the synthetic coatings of transplanted medical devices, such as pacemakers. For many bacteria, the ability to attach to the surface of a host cell is an essential first step in the infection process. Dr. Lin will determine the three-dimensional structure of the enzymes that synthesize these teichoic acid polymers using x-ray crystallography, a technique that can deduce the atomic structure of molecules. A lack of teichoic acid significantly destabilizes the bacterial cell wall. Dr. Lin is looking for ways in which this information can be used to develop ways of interfering with the ability of bacteria to attach to host cell surfaces as a first line of defense in protecting against the establishment of bacterial infections.

A protease is an enzyme that can split a protein into peptides. Alterations in normal protease expression are known to be involved in the development of cancer, arthritis and various lung, neurological and cardiovascular diseases. As a result, many proteases and their substrates are an important focus of attention as potential drug targets. Among proteases, matrix metalloproteases (MMPs) are responsible for the proteolytic modification of the extracellular matrix, a complex network of polysaccharides and proteins secreted by cells that serves as a structural element in tissues and also influences their development and physiology. While more is being learned about the multiple functions of MMPs –, many of which are beneficial – their roles and biological functions are not fully understood. David Rodriguez’s research seeks to unravel the complex web of connections among MMPs, their natural substrates, inhibitors and other proteases. He is using a technique known as Mass Spectrometry to detect and identify hundreds, even thousands, of proteins in a sample. By identifying and describing the complex set of signaling pathways in which MMPs are involved, Rodriguez is hoping to better understand the role of these proteases and to predict the consequences when they function abnormally. Such knowledge is critical for designing more effective drugs to treat diseases which result from abnormal protease function.

Spinal cord injury mostly occurs in young people, causing debilitating, lifelong disability. Stroke mostly occurs in older people, and is a leading cause of disability in the elderly. In both cases, recovering function relies on the ability of the central nervous system (CNS) to rewire itself. But the CNS isn’t very supportive of the integral processes required for rewiring to occur. Rewiring requires nerve cells to sprout new fibres (called axons) and subsequently make new connections in the spinal cord by bypassing the damaged area. Rewiring also relies on the birth of new cells that must migrate to the injury site and replace cells that died as a result of the injury. Finally, new blood vessels must also grow back into the damaged area to sustain the regeneration of the new tissue. Each of these processes is controlled by the “extracellular matrix,” the environment surrounding cells. Dr. Adele Vincent is examining how this matrix can be manipulated to improve repair processes in the central nervous system. She is investigating whether SPARC, a protein that regulates interactions between cells and the extracellular matrix, can be used to promote recovery after stroke. Dr. Vincent is studying the role of SPARC in regulating processes that impact on nerve regeneration after injury, such as neural stem cells, new blood vessel formation, and the inflammatory response. Ultimately, these findings could lead to more effective therapies to stimulate regeneration following traumatic injuries, stroke and neurodegenerative diseases.

The type 3 secretion system (T3SS) is a multi-protein complex that plays a central role in the virulence of many bacteria categorized as Gram-negative. Gram-negative bacteria include some of the most harmful bacteria to humans and plants. T3SS directs the secretion and transfer of bacterial proteins into the cytoplasm – the portion of the cell outside the nucleus of eukaryotic cells. It’s known that the secretion system is composed of about 20 to 25 different proteins arranged into two distinct parts called the needle complex and the translocon. However, the exact mechanisms of how proteins are secreted by T3SS and the precise molecular organization of the complex are poorly understood. Dr. Neta Wexler Sal-Man aims to define, at the molecular level, the interactions of proteins that create the secretion apparatus of two pathogenic bacteria: Enteropathogenic E. coli and enterohemorrhagic E. coli. In the long term, she hopes to identify a way to manipulate the secretion system in order to inject desired proteins or molecules into eukaryotic cells. The research will help improve understanding of this highly complex type 3 secretion system and could ultimately contribute to the design of new therapeutic drugs aimed at the potentially deadly bacteria that use T3SS.

The strict regulation of our heart rates allows our bodies to adapt to changing conditions to provide the different parts of our bodies with the appropriate amounts of oxygen and nutrients. Cardiac arrhythmias, or irregularities in the heart rate, can have devastating consequences such as heart attack or stroke. Understanding the basis for heart rate regulation may improve our current ability to treat and prevent cardiac arrhythmias. Voltage-gated potassium (Kv) channels are proteins in the heart tissue that play a critical role in the regulation of heart rate. Kv channels open and close depending on the electrical activity with in the heart. By allowing potassium ions to exit the heart muscle cells, Kv channels indirectly regulate whether the cells (and hence heart) will contract, or beat. After the channels open, they often undergo a process known as inactivation which causes the channel to close and prevents potassium flow. The rate at which channels enter and exit inactivation plays an important role in determining heart rate. May Cheng is studying the inactivation properties of two Kv channels found in the heart, Kv1.5 and Kv4.2. Kv1.5 has been implicated in atrial fibrillation, and Kv4.2 is believed to play a role in ventricular fibrillation. By increasing our understanding of the basic processes behind potassium channel inactivation, this research may lead to future therapies to treat cardiac arrhythmias.

Parvoviruses are small, single stranded DNA viruses that must enter the nucleus of their host cells in order to replicate. Because of their ability to target and kill rapidly dividing cancer cells, parvoviruses have recently gained attention as potential vectors (carriers) for use in cancer gene therapy. Although research has led to a better understanding of cell entry and trafficking of parvoviruses, little is known about how parvoviruses are imported into the nucleus. Sarah Cohen is continuing her earlier MSFHR-funded research which examined how a specific parvovirus, Minute virus of mice (MVM), enters the cell nucleus. Cohen’s research discovered that MVM selectively breaks down the membranes surrounding the nucleus, the nuclear envelope (NE), in the early stages of infection. Now, she is investigating how parvoviruses disrupt the nuclear envelope of host cells and whether this disruption allows the MVM access into the cell nucleus. Cohen’s goal is to determine whether parvoviruses initiate the process leading to cell death (apoptosis) early in an infection. If so, it may be possible to boost the anti-cancer activity of parvoviruses, by engineering them to produce additional proteins that can kill cancer cells. Ultimately, this research could show MVM is a viable anti-cancer agent for clinical studies.

Rheumatoid arthritis affects one in six people. Although the specific trigger is unclear, the condition occurs when the immune system mistakenly attacks tissue within the joints. Symptoms include swelling, pain, stiffness and redness caused by an accumulation of white blood cells in and around the joint. When the inflammation persists for a long time, it may cause irreversible cartilage damage and bone erosion, leading to deformity and disability. In her previous MSFHR-funded research, Jennifer Cox examined molecular influences on the immune system. Now she is focusing on understanding the inflammatory process in the development of arthritis. Jennifer is studying MMP-8, a member of a family of enzymes called matrix metalloproteinases that function to break down proteins in the body. This process, called proteolysis, is essential for normal immune responses. However, an unusually high level of MMPs may contribute to diseases such as arthritis and cancer. For example, elevated levels of MMP-8 are present in patients with rheumatoid arthritis. Jennifer is researching whether MMP-8 contributes to the progression and severity of the disease, or conversely if the high levels of enzyme are protecting against inflammation. Her findings will contribute to a better understanding of the inflammatory process and potentially to new methods for treating rheumatoid arthritis.