Multifunctional immunomodulating conjugates for targeting and treating glycocalyx dysfunction in inflammatory conditions

Diseases that involve the heart or blood vessels, autoimmune diseases (e.g. diabetes, multiple sclerosis), or the rejection of transplanted organs affect about 1 in 3 Canadians and constitute a significant cost to the Canadian economy. In the perpetuation of these diseases glycocalyx shedding plays a key role. The glycocalyx (literally meaning “sugar coat”) is a sugar polymer-based structure that covers the surface of the cells, which are lining all organs and blood vessels. It lies at the interface between bloodstream and organ tissue and represents the protective front line against inflammatory and immune-mediated diseases. Thus, we aim to specifically target and treat glycocalyx dysfunction by rapidly rebuilding it through a new cell surface engineering approach, which should enable organs to maintain or reestablish their function. To do so, we will develop polymer conjugates which can selectively bind and retain on the endothelial cell surface. The conjugates will present sugar moieties which resemble the natural glycocalyx layer. We anticipate to realize a novel approach with significant therapeutic potential to improve treatment for diverse disease conditions where glycocalyx dysfunction is contributing to the pathology.

New enzymes and processes for the removal of cell surface antigens from red blood cells to generate ‘universal donor’ O type blood for transfusion

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.

Placental proteomics: Gaining a system-wide understanding of the dynamic protease networks in normal placental tissue and upon inflammation to identify diagnostic signatures as biomarkers for preterm labor

Preterm birth affects approximately 12 percent of all deliveries. Prematurity is the leading cause of neo-natal mortality in Canada and is a major risk factor for impaired growth and development. There is a pressing need for tests to predict the risk of premature delivery accurately enough to provide the best treatment to prevent pre-term delivery and avoid unnecessary interventions.

It is thought that preterm labour can result from infection and inflammation of the placenta. Fetal and/or maternal inflammatory proteins in threatened preterm labour may form a diagnostic signature that can be used to predict whether preterm delivery is imminent or not. The Overall lab has developed several techniques to identify diagnostic inflammatory signatures in tissues. Using these methods, Dr. Eckhard aims to establish a functional, system-wide understanding of infection-induced inflammation in preterm labour using human placentas as a model of infection and inflammation.

Dr. Eckhard will elucidate placental molecular pathways that are activated in response to escalating infection resulting from the rupture of placental membranes. Collection of placentas from various documented times following membrane rupture to delivery will capture a range of inflammatory responses to infection — these “timed infection” placentas will be compared to non-inflamed placentas from full-term caesarean section deliveries and to placentas from defined pre-term deliveries to establish biomarkers and determine how infection-induced inflammation leads to pre-term labour.