Apicomplexa and microsporidia are two groups of parasites that infect a broad range of animals, including humans. Apicomplexa cause serious diseases such as malaria and encephalitis. Traditionally, microsporidia were not prevalent among humans. However, microsporidia are increasingly becoming a problem in people with impaired immune systems. The relationships of these parasites to other organisms and how they evolved are not clearly understood. Yet recent molecular studies have revealed surprising evolutionary histories for both groups of parasites. Apicomplexa evolved from an alga, an unusual origin for a parasite. Microsporidia were originally believed to be simple, single-celled organisms that were not highly evolved. But we now know that microsporidia have evolved from fungi. I am studying the evolution and biology of apicomplexa and microsporidia to learn how they developed into parasites and how they function. This research may uncover weaknesses in the parasites that can be exploited to develop new treatments for disease involving herbicides or fungicides that would not have been considered earlier.
Research Pillar: Biomedical
Functional imaging of neuronal Ca2+ in vivo and in vitro brain slice
My research lab uses fluorescence imaging technology combined with electrophysiological measurements to study problems with the transmission of information in the brain. Such problems are the foundation of numerous brain disorders including schizophrenia, depression and Parkinson’s disease. We need a thorough understanding of the brain’s communication process to understand and develop treatments for these disorders. Brain function depends on the activity of neuronal circuits, which are formed by thousands or millions of neurons (nerve cells) that communicate with each other at points of contact called synapses. Neurons communicate when the pre-synaptic neuron releases a chemical transmitter that diffuses across the synaptic space and binds to receptors on the post-synaptic (receiving) neuron. The receptors are often located on branches of the neuron called dendrites. My research examines the factors that control the amount of chemical transmitter released, and in particular, the regulation of release by calcium ions in pre-synaptic neurons. Transmitter release is stimulated by an influx of calcium into the pre-synaptic neuron. Calcium influx is controlled by changes in the electrical potential of the pre-synaptic neuron that regulate the opening and closing of the voltage sensitive “”gates”” of calcium permeable pores in the neuron’s surface. By changing calcium influx and accumulation in neurons, the strength of the synaptic connection can be varied to adapt to new conditions or tasks. Using fluorescent dyes that are sensitive to calcium, we monitor calcium in pre-synaptic neurons at the same time that we measure synaptic transmission electrically. Our laboratory has the unique capability to make these measurements in an intact living mammalian brain. We are investigating how activity in the pre-synaptic neuron and substances such as dopamine or serotonin control transmitter release by their effects on calcium, and the biochemical machinery that release transmitter in response to calcium. We also are studying how the signal reception at the post-synaptic neuron is regulated by electrical properties of the dendrites.
The role of the hematopoietic progenitor antigen, CD34 on mature mast cells
A study that Erin Drew took part in revealed some surprising insights about the mysterious CD34 protein. Contrary to the predominate belief that this protein is absent on mature blood cells, this study demonstrated that CD34 is present on mature mast cells. These cells play a major role in the development of asthma and allergies by releasing strong chemicals such as histamine into tissues and blood. In her Master’s research, Erin further investigated the role of CD34, and a similar protein CD43, on mast cells. Her research suggests that CD34 blocks inappropriate cell adhesion, and that CD34 and CD43 play an important role in the appropriate migration of cells into tissues. Erin hopes this work could lead to new drug treatments for asthma and allergies, as well as contribute to the emerging use of stem cell transplantation in treatment of diseases.
The role of BDNF in progesterone and estradiol effects on cell proliferation, survival and cell fate in the dentate gyrus of adult female rats following contusion
Research has revealed that adult humans and all other mammals are unique in their ability to generate new brain cells as part of a process called neurogenesis. After a traumatic injury, estrogen and progesterone (female steroid hormones) and the Brain Derived Neurotrophic Factor (BDNF) protein help the brain recover. Jennifer Wide’s Masters research focused on the interaction between estrogen and neurogenesis, and in particular, the effects of chronic estradiol treatment on neurogenesis. Based on previous research, she hypothesized that changes in neural structure affect cognition, such as through working memory (also known as short-term memory). She studied, therefore, the effects of estradiol treatment on acquisition and reacquisition of working memory. The research demonstrated that chronic estradiol treatment has a significant differential effect on working memory, especially in low doses. Increasing understanding of neurogenesis will bring researchers closer to the goal of replacing lost cells throughout the brain and have a major impact on neurotrama and neurophsychiatric disorders.
Regulation of the transcriptional activator, beta-catenin, by the B cell receptor
Sherri Christian is studying a process that’s integral to the immune system: the development of B cells that produce antibodies – immune cells that attach to and destroy infectious microbes and other harmful agents. Signals from within and outside B cells direct the multi-stage process by which these cells develop. Christian is investigating the nature of these signals and specifically examining the regulation of a protein called beta-catenin. The protein’s importance in the development of other cell types suggests it may play a similar developmental role in B cells. Christian hopes that increasing understanding of B cell development will ultimately lead to therapies for prevention of disease, such as cancer, which occurs when the normal process of cell development goes awry.
Comparative and functional genomic analysis of a gene dense, GC rich region at chromosome 7q22 associated with myeloid leukemias and male infertility
Michael Wilson’s doctoral research focuses on a fragile region of the human genome, 7q22, which has been linked to leukemias, hemochromatosis (a genetic disease that causes excessive build-up of iron in body tissues), male infertility and schizophrenia. Besides preparing a detailed map of all 7q22 genes and elements that regulate their expression, Wilson is also working with a bioinformatics group at Penn State to design a web-based program that interactively displays the gene sequence data. He is also investigating the function of two specific genes, including one that plays a role in fertility. Wilson hopes the research will provide essential information for narrowing in on cancer and schizophrenia-related genes, and also provide insight into male infertility.
Characterization of retinoschisin, the protein involved in X-linked juvenile retinoschisis
X-linked retinoschisis is the most common form of retina damage in young males. Symptoms of the genetic disease include splitting of the retina’s inner layers, blood vessel rupturing and sometimes blindness. It is often undiagnosed or misdiagnosed due to diverse changes in the retina that can occur. Winco Wu is investigating the nature of the retinoschisin protein, produced by the gene that causes the disease. He is selectively examining mutations of retinoschisin and determining the protein’s exact size, whether it binds to other molecules, and how it interacts with other proteins and its own subunits. Improving understanding of retinoschisin will further knowledge of how retina deterioration occurs, and may ultimately lead to therapies for diseases such as X-linked retinoschisis. Learning about the protein will also shed light about proteins with similar characteristics that are involved in cancer and nervous system development.
Gene Therapy for a genetic cardiovascular disease: AAV-mediated gene transfer of a powerful, naturally occurring, LPL-S447X variant for the treatment of LPL deficiency
Dr. Colin Ross believes that studying genetics and diseases at the molecular level can open many doors for the treatment of diseases at their root causes. He’s doing exactly that in cutting edge research to develop treatments for a genetic cardiovascular disease that has the highest worldwide frequency in Canada’s French-Canadian population. People with lipoprotein lipase (LPL) deficiency are missing a key enzyme that helps break down triglycerides (fats) in the blood stream. Elevated levels of these fats can cause serious, life-threatening damage to the pancreas, heart and other organs. Ross is working on the development of gene therapy techniques to implant healthy genes into cells to restore production of the missing enzyme. He ultimately aims to develop a safe and long-term treatment for LPL deficiency.
P-glycoprotein, ABC transporters and genomics in cancer research
My research focuses on genes that play a role in the development of cancer, with a particular interest in genes that help malignant cells survive by limiting the effects of anti-cancer drugs. Our research team was the first to discover a protein (P-glycoprotein) on the surface of cancer cells that resists multiple cancer drugs. The protein protects cancer cells by pumping out drugs before they inflict lethal damage. With recent advances in genome science, the team has learned that proteins similar in structure to this one are present in more than 50 genes in the human genome. What these genes do in normal cells or in malignant ones is not yet fully understood. This is one of the questions that our team of more than 40 clinicians and scientists in the Cancer Genomics Program are working to answer. By analyzing how these genes act in normal tissue, and in cancers that are or are not responsive to drug therapy, we hope to identify markers (changes in the molecular structure or function of cells) that will be useful in diagnosing specific cancers earlier. Our goal is more effective treatment and, better still, more effective preventive measures.