Human blood comes in four major "types" — A, B, AB and O — which differ in the sugars on their red blood cells (RBCs). Correctly matching blood types before transfusions is essential to avoid immune responses that can be fatal. O type blood is known as a universal donor since RBCs from an O type person can be transfused into A, B, AB or O type individuals without harm. It is used in emergencies when there is no time to type the patient or the correct type is unavailable. Type O blood is often in short supply.
A and B type blood can be converted to universal O type blood by using specific enzymes to clip off the extra sugars: once clipped the original sugars are not reformed since mature RBCs have lost that ability. However the enzymes available have not been efficient enough. The Withers lab recently discovered efficient enzymes for this within the human gut microbiome. In conjunction with the Centre for Blood Research, they have proven their efficiency and converted whole units of blood. This proposal is primarily to carry out the pre-clinical evaluations needed, and in conjunction with Canadian Blood Services, move this technology forward. This will open up access to universal donor blood, thereby helping alleviate shortages.
Research Location: Michael Smith Laboratories
Developing effective antimicrobials using novel quorum quenching enzymes
Antibiotics revolutionized our medicine against pathogen infection. However, pathogenic bacteria have recently evolved resistance to multiple antibiotics, becoming a global health care risk. We urgently need to develop novel strategies to combat antibiotic resistance and develop evolution-proof antibiotics.
Dr. Han’s research will study and engineer enzymes that could be used as potential antibiotic reagents to degrade a key chemical molecule that bacteria utilize to develop virulence and resistance to antibiotics (biofilm formation). Specifically, Dr. Han will look to discover novel enzymes and perform detailed profiles of these enzymes to interpret their molecular mechanisms. Using state-of-the-art enzyme engineering and laboratory evolution techniques, he will engineer these enzymes for higher stability and functionality and demonstrate anti-virulence and anti-biofilm capabilities of these engineered enzymes, crucial for biotechnological and pharmaceutical applications.
This research program will provide the first mechanistic study of enzymes that disrupt the virulence of diverse pathogenic bacteria, and could have significant impact in the field. Most importantly, this research could provide novel and effective tools to control bacterial population and infection, crucial in the fight against the development of antibiotic resistance.
Sudden Unexpected Death in Epilepsy (SUDEP): A new model for mechanistic and therapeutic investigation
Epilepsy is one of the most common brain disorders. The condition is characterized by uncoordinated brain electrical activity and recurrent seizures. Epilepsy patients may die unexpectedly with unknown cause, a phenomenon termed “sudden unexpected death in epilepsy” (SUDEP). SUDEP accounts for about 50% of deaths in individuals suffering from drug-resistant epilepsy in which severe seizures are followed by alterations in respiratory and cardiac functions.
The underlying mechanisms triggering SUDEP remain unknown. Using animal models of human disease and live brain imaging, Dr. Thouta’s research will work to define the specific brain regions that promote brain inactivity during SUDEP-like seizures. This will include testing novel anti-epileptic drugs as a potential preventative SUDEP agent.
The results of this research will provide an understanding of the cause of SUDEP and could have a significant impact on epilepsy drug development efforts, potentially leading to the discovery of novel therapeutics for SUDEP prevention.
Tying the gut in knots: Characterizing how pathogenic E. coli transform the gut cell landscape
Diarrheal disease affects 1.7 billion people every year, killing around 760,000 children. A leading cause of this disease are bacteria like enteropathogenic Escherichia coli (EPEC). EPEC’s ability to cause disease relies entirely on creating an environment in which it can thrive. EPEC achieves this by secreting “effector” proteins directly into human host cells, which rewire the human cell, allowing EPEC to take control of cell immune signalling. One way effectors work is by chemically modifying host proteins with phosphate groups (phosphorylation), which may alter how proteins interact with one another.
Dr. McCoy’s research will develop a method for studying the interaction between bacteria like EPEC and their human hosts. His preliminary data has shown that a group of drugs called bumped kinase inhibitors (BKIs) can block this interaction. Expanding on this, he will aim to reveal how EPEC uses phosphorylation to manipulate the human host and establish infection.
Post-translational modifications as a virulence strategy of diarrheagenic E. coli
With an estimated 1.5 million fatal cases among children and about 2 billion cases total annually, diarrheal diseases are a significant cause for morbidity and mortality worldwide. Enteropathogenic and enterohemorrhagic E. coli (EPEC/EHEC) are two forms of diarrheagenic E. coli that cause these diseases. EPEC provokes potentially fatal infantile diarrhea and EHEC triggers severe diarrhea, which can progress to fatal renal failure. Both pathogens infect epithelial cells of the host intestine. They utilize a sophisticated delivery system, the type III secretion system, to inject specialized effector proteins into the host cytosol. Once translocated, these effectors trigger signaling events to subvert host cell functions and cause disease. However, only little is known about respective host targets and mechanistic details.
Dr. Scholz’s research aims to clarify if and how EPEC/EHEC utilize effectors to interfere with the host posttranslational modification (PTM) machinery and thus with host signaling to promote disease. His research will represent the first comprehensive analysis of the role of PTMs in EPEC/EHEC pathogenesis and will provide new strategies for therapeutic approaches against bacterial pathogens.
Throughout his study, Dr. Scholz plans to pursue identified host targets, elucidate the mechanistic details of this effector-host target interplay and clarify its consequences for pathogenesis. Having already established a highly efficient, reliable and comprehensive screening approach for phosphorylation, a common and pivotal PTM in host signaling, he further plans to employ similar strategies to target also other types of PTMs, such as ubiquitination, and define their role during EPEC/EHEC infection.
Dosage CIN genes: A comprehensive analysis of gene dosage effects on genome stability
Chemotherapy is one of our strongest weapons for treating cancer, but it also harms healthy cells and causes serious side effects in patients. Researchers at the Hieter Laboratory at the University of British Columbia in Vancouver hope to develop a more targeted approach, one that takes advantage of the genetic changes that exists in cancer. Their approach identifies which combination of genetic changes will selectively kill cancer cells. Answering that question will be key to developing new targeted drugs to fight cancer.
Cancer cells often contain multiple gene mutations or changes which affect the stability of the genome, but whether this instability is a cause or consequence of cancer remains to be understood. A project led by Dr. Supipi Kaluarachchi Duffy is using high throughput genetic screens, overproducing one gene at a time in yeast, to identify which genes lead to genome stability. She will then identify genetic changes that are common in both yeast and human cancers and leverage these to find secondary genetic targets. Yeast is a great model organism for this work because it shares many of the fundamental biological pathways that are essential for life.
“The first step is distinguishing between a gene whose overproduction contributes to genome instability and a gene that has no effect,” says Duffy. “The end result would be more targeted chemotherapy at lower doses and with fewer side effects.”