Rhythmic electrical impulses that drive beating of the heart and sleep waves in the brain are controlled by natural pacemakers called ion channels. Pacemaker channels act as electrical switches, and they switch on faster when they bind natural chemical messenger molecules called cyclic nucleotides (CNs). This is thought to involve temporary structural changes in the region of the channel molecule that interacts with the CNs. By modifying the structure of the CN-binding region in the channel and observing how this affects switching, Dr. Edgar Young is studying what structural features of the channels help or hinder this process. Gaining a better understanding of the structural changes that allow switching may lead to the development of new drugs to control pacemaker acceleration, which could alleviate problems such as accelerated heartbeats or epileptic seizures.
Program: Scholar
Protein traffic at nascent neuronal contacts
Neuronal impulses in the brain are transmitted across synapses, which control brain function by facilitating the firing of neurons (excitatory synapses) or restricting it (inhibitory synapses). An imbalance in this process is thought to underlie several neurological diseases, including Alzheimer’s disease, mental retardation, autism, schizophrenia and epilepsy. Dr. Alaa El-Husseini was previously funded by MSFHR to support his research into the study of a post-synaptic density protein (PSD-95) that stimulates the formation and maturing of the synapses that release glutamate, a key neurotransmitter. He has also determined that this protein affects the balance of excitatory and inhibitory contacts induced by neuroligins, a family of cell adhesion molecules. Dr. El-Husseini’s current research focuses on how these proteins assemble at the synapse, uncovering the molecular mechanisms that govern the trafficking and function of these proteins to determine how their manipulation may affect synaptic balance.
The endothelium: Function and dysfunction
The interior lining of blood vessels is known as the endothelium. Endothelial cells, which make up this inside layer of all blood vessels, are remarkably responsive to changes that occur in the blood and tissues, both under normal conditions and in disease states, sending signals back to the blood and tissues to organize a response. Endothelial cells initiate and direct the growth of new blood vessels within a tissue that is not receiving a sufficient supply of oxygen and nutrients. This growth of new blood vessels can be either beneficial or detrimental to a person’s health. When blocked blood vessels are contributing to the lack of sufficient blood supply (e.g. hardening of the arteries or diabetes), the body’s creation of new blood vessels can prevent tissue damage and promote healing. However, new blood vessels also required for cancer growth by providing the tumour with the oxygen and nutrients it needs. Dr. Aly Karsan is studying several molecules on the surface of endothelial cells to determine how they regulate the growth of new blood vessels. With greater knowledge about the molecular processes underpinning blood vessel growth, he hopes to identify new ways to either promote or restrict these processes to combat a variety of diseases.
Reduction in microsporidian parasites
Microsporidia are a group of parasites that can only reproduce by invading and taking over an animal cell. They are highly dependent on their host cell for nutrients and energy, which has allowed them to discard genes for many metabolic proteins and evolve unique ways to carry out other essential activities. For example, microsporidian genomes are among the smallest of any complex cell. As the genomes shrink, critical information controlling gene expression has been squeezed from its conventional location. The mitochondria—known as the powerhouse of the cell—is also reduced nearly beyond recognition in form and function. In both these systems, the microsporidia do things differently from other cells, including the host animal cell in which they reside. Dr. Patrick Keeling is studying the effects of a shrunken genome and mitochondria in microsporidia, investigating how these reductions affect the way the parasite expresses its genes and targets proteins for function. Fully understanding these unique characteristics is important because, as with other parasites, such features could be exploited as targets for therapy.
Gene and cell therapy approaches to treat diabetes
Transplantation of pancreatic islets has proven to be effective in controlling blood glucose levels in subjects with type 1 diabetes. The results of this procedure have demonstrated the potential to treat diabetes by transplanting as little as a teaspoon of insulin-producing cells into a diabetic patient. However, the promise of this procedure is currently restricted by two major challenges: transplantation is dependent upon the availability of tissue from recently deceased individuals; it also requires the use of chronic immunosuppression in the recipient, which carries the risk of side effects. Dr. Timothy Kieffer is investigating a variety of approaches to achieve the results of islet transplantation without relying on donor tissue. Ideally, he hopes to develop a therapy that uses the patient’s own cells and stimulates either the regrowth of insulin-producing beta cells, or the generation of new cells from adult stem cells. His team is also looking at ways to genetically modify the body’s gut cells to produce insulin or other anti-diabetic factors automatically in response to eating a meal.
Genome-scale variation in health and disease
The sophisticated approaches of genomics are increasingly being used to analyze the majority of the genetic material contained within cells. The tools of genomics have catalyzed remarkable developments in health and disease research. These tools continue to evolve at a rapid pace, making possible additional health research opportunities that are increasingly comprehensive. Dr. Marco Marra is Director of the British Columbia Cancer Agency Genome Sciences Centre. Dr. Marra was funded as an MSFHR Scholar in 2001, with a specific focus of using genomics to comprehensively search for genes that play roles in cancer. In 2003, Dr. Marra also distinguished himself as leading the team that cracked the genetic code for SARS. In addition to his continuing work in cancer genomics, Dr. Marra is also working to identify and analyze DNA mutations correlated with, or causing, mental retardation. A consistent theme in Dr. Marra’s research is the identification and analysis of new genes and new gene products to determine their potential for use as new therapies or vaccines to combat cancer, infectious diseases, and other disorders.
Applications of bioorganic chemistry to medicine
Chemistry plays a central role in uncovering the mysteries of biology, and in the generation of new ways to approach diagnostics and disease therapies. An exciting area for health research is in the development of synthetic chemistry – the creation of “man made” molecules that contain properties that regular DNA does not possess. This merging of chemistry and biology towards medically relevant goals—such as developing antiviral compounds or radiopharmaceuticals for diagnostics or treatment—represent a powerful combination. Dr. David Perrin’s work involves the creation of synthetic DNA and peptides that may be useful in recognizing, imaging and ultimately interfering with or halting disease processes. He generates new molecules based on amino acids and nucleic acids, which have potential for disrupting RNA activity in diseases such as cancer or HIV. In addition to researching the use of synthetic DNA in disease therapies, Dr. Perrin has developed a new class of PET imaging (Positron Emission Topography) probes for the efficient radiolabelling of biomolecules. These biomolecules have the potential to image and possibly eradicate cancer directly or permit more precise monitoring of its progression in conjunction with other targeted therapies.
The role of RNA in the evolution of life
One of the fundamental issues facing biology is the question of our origins. Despite the fact that time and evolution have erased much information about early life on earth, a number of fascinating clues remain within cells that have led to the proposal of an “RNA world” hypothesis – the premise that RNA (ribonucleic acid) was once the dominant biological catalyst, capable of important metabolic functions that are currently performed by protein enzymes. Dr. Peter Unrau is exploring the chemical versatility and evolutionary potential of RNA. He has been examining the ability of RNA to replicate independent of protein. Along with his chemical interests in RNA, he is also exploring the processing of RNA by eukaryotes (cells with a distinct membrane-bound nucleus) and studying the interaction of small RNA processing and viral replication in plants and humans.
Targeting the beta cell for Diabetes therapy
In healthy people, blood glucose levels are tightly controlled by insulin, a hormone produced by beta cells in the pancreas. When the blood glucose elevates (for example, after eating food), insulin is released from the pancreas to lower the glucose level. In type 1 diabetes, beta cells are destroyed by one’s own immune system. In type 2 diabetes, insulin secretion from beta cells is insufficient and beta cells are gradually lost due to the toxic effects of fats, high glucose levels and build-up of toxic amyloid deposits in the pancreas. Dr. Verchere’s research is focused on understanding how beta cells normally function in health, and what goes wrong in diabetes. He is investigating why toxic islet amyloid deposits form and how they kill beta cells, as well as how immune cells kill beta cells in type 1 diabetes. He is also looking at ways to protect transplanted beta cells from immune destruction. His long-term goal is to develop novel therapies that enhance beta cell survival and function in type 1 and type 2 diabetes.
Characterization of oligodendrocyte abnormalities in schizophrenia
Schizophrenia is a severe psychiatric illness affecting approximately one per cent of Canadians. While the causes are not yet fully understood, it is thought that the symptoms of this disorder may arise from abnormalities in nerve fibre connections between different brain regions. Mounting evidence suggests that a contributing factor may be abnormalities in myelin, the fatty insulating substance that surrounds nerve fibres and speeds up the transmission of nerve impulses. Studies have shown reduced density of oligodendrocytes, the brain cells that produce myelin, and altered expression of several proteins found specifically in myelin—suggesting a possible source for impaired transmission of nerve impulses between brain regions. Through a series of investigations Dr. Clare Beasley is examining the role of oligodendrocytes in schizophrenia. She will characterize oligodendrocyte alterations in the brain in schizophrenia and examine their relationship with myelin proteins and lipids. By better understanding the connection between abnormalities in these myelin-producing cells and the symptoms of schizophrenia, she hopes to shed light on the cause of this devastating disorder.