Research and scholarly activity

Primary investigator: Dr. Ted Lakowski

Mixed Lineage Leukemia is a childhood cancer that is difficult to treat and has a poor prognosis. It is caused by overexpression of the oncogene Homeobox protein A9 (HOXA9). The lysine methyltransferase (KMT) DOT1L methylates histone H3 at K79 (H3K79Me) in the HOXA9 promoter increasing its expression. Studies have shown that decreasing HOXA9 expression is sufficient to treat the disease. Inhibitors of DOT1L also reduce HOXA9 expression and are in clinical trials as a treatment for mixed lineage leukemia, however, initial results show that they have poor efficacy and dose limiting toxicities. DOT1L is active at multiple promoters, and we have shown that DOT1L inhibitors and drugs targeting epigenetic enzymes in general, alter the expression of many genes, likely leading to decreased efficacy and off-target effects. Therefore, to improve their efficacy and decrease adverse effects, DOT1L inhibitors should be targeted to the HOXA9 promoter. In this project the student will recombinantly express and purify DOT1L, and then measure its activity and inhibition in vitro using liquid chromatography tandem mass spectrometry (LC-MS/MS). Inhibitors in various phases of clinical trials will be tested in addition to broad spectrum methyltransferase inhibitors. The results will assist in the development of new inhibitors of DOT1L that are gene specific. Such inhibitors will be a new class of therapeutic for the treatment of Mixed Lineage Leukemia that will be more effective, while reducing required dose and toxicity compared to conventional DOT1L inhibitors

Primary investigator: Dr. Christine Leong

This research focuses on drug utilization and optimizing medication use in primary care. Specific areas of focus include polypharmacy and psychotropic medication use. Pharmacoepidemiology, systematic reviews and mixed methods studies are primary methods used in my program. Current projects include:

1. A survey study on patient values and preferences with respect to communicating risk versus benefit of benzodiazepine and z-drug initiation, and
2. Linking data on addictions to administrative databases to study long term outcomes of substance use.

The undergraduate student will be involved in data entry, literature searches, survey development, and data extraction. There may also be opportunities for manuscript writing and conference presentation.

Primary investigator: Dr. Lucy Marzban

Diabetes is the most common endocrine disorder worldwide. Two major types of diabetes are Type 1 (T1D; Juvenile onset) and type 2 (T2D; adult onset) diabetes. In both types of diabetes pancreatic islet beta cells fail to produce enough insulin leading to elevated blood glucose but the underlying mechanisms are different.

In patients with T1D, beta cells are destroyed by the body’s immune system, leading to lifelong insulin therapy. Islet transplantation has provided a feasible approach for treatment of T1D but is currently limited by low number of available pancreatic donors and short-term survival of transplanted islets. Both immunologic and non-immunologic factors contribute to islet graft failure in diabetic patients.

Formation of toxic protein aggregates, named islet amyloid, is one of the important non-immunologic factors that contributes to impaired beta-cell function and death in transplanted islets leading to islet graft failure.

Studies in our group focus on exploring the mechanisms by which amyloid causes beta-cell death in islet grafts and develop new therapeutic strategies to protect transplanted islets from amyloid toxicity thereby prolonging islet graft survival in T1D patients.

Students who join our research group will learn how to culture islets, prepare islet sections, immunolabel live and fixed cells/tissues, and use imaging techniques. Students will also develop problem-solving, data analysis, and presentation skills by participating in our regular lab meetings.

Primary investigator: Dr. Jillian Stobart

Pericytes are cells found on brain capillaries. Exciting new evidence suggests that pericytes may regulate the blood-brain-barrier and dilate capillaries to increase blood flow where needed. Both of these roles are essential for brain health and pericytes may become dysfunctional or die during disease, such as stroke or Alzheimer’s disease.

Our research focuses on calcium signalling in pericytes, which is likely important for regulating blood flow. We want to know: what causes calcium signals in pericytes? What happens as a result of these signals? These questions are fundamental for understanding pericyte physiology and their role in the brain. This work may also lead to future development of pericyte-specific drugs for therapeutic use.

Students who join our energetic team will have the opportunity to work directly with mice, including mouse handling, training, and injections. Students will also learn two-photon microscopy, the latest, state-of-the art microscopy technique in neuroscience. They will use this microscope to record movies of beautiful, never-before-seen calcium signals in pericytes in the brains of live mice in real-time.

Students will also gain valuable computer skills by learning to analyze these calcium movies through programs such as MATLAB and R. Students will also develop communication and problem-solving skills by participating in regular lab meetings in a group setting.

Primary investigator: Dr. Geoffrey Tranmer

This group is in the process of preparing to file a patent for a series of anticancer agents with the assistance of a patent agent and the University of Manitoba Technology Transfer Office.

The primary investigator has been instructed not to disclose the general structure of the molecules to be patented; however, we can provide a brief overview of the project below.

The summer student will synthesize new analogs relating to this patent application and assist in the study of the anticancer properties of the compounds using various biochemical assays. This is a medicinal chemistry project where the student will synthesize new molecules on a daily basis, and assist in the testing of their anticancer properties with the help of a doctoral student. Additionally, the student may also perform some in vitro cell based assays, following proper training.

Overall, the student will spend the summer making new anticancer molecules relating to our provisional patent that will lead to the development of next generation topoisomerase I inhibitors (an approved class of anticancer agents).

Primary investigator: Dr. Dake Qi

Olanzapine is one of the major atypical antipsychotics which has been widely used in the clinical therapy of severe mental illness, such as schizophrenia. However, this drug as other atypical antipsychotics significantly induces metabolic side-effects, including obesity, insulin resistance and even diabetes.

Our recent study indicated that olanzapine induced metabolic dysfunction is probably through a classical cytokine, macrophage migration inhibitory factor (MIF). Following olanzapine treatment, plasma MIF levels are significantly upregulated in animal models and human schizophrenic patients.

The increased circulating MIF may contribute to regulate food intake in the “appetite” center, hypothalamus. However, so far the molecular mechanism is largely unknow.

Our present project is designed to explore how olanzapine modulates MIF expression and release in neurons. We will majorly use neural cell lines to test the responses in genes and cellular signaling transduction following olanzapine treatment. We expect the findings will be further investigated in in vivo animal models in the coming future.