PhD, Cornell University
Type 1 diabetes in rodent and human diseases
Type 1 diabetes (T1D) results from autoimmune destruction of beta cells in the pancreas, the only cells that make the vital hormone insulin. Despite daily insulin injections, individuals with T1D have an increased likelihood of heart disease, stroke, kidney disease, and blindness. T1D is caused by multiple genetic risk factors and poorly defined environmental factors. The incidence in Canada and other developed countries has been rising at the rate of 3-5 per cent, per year over the past 50 years. There is strong evidence that variations at many genes confer T1D risk; however, our genes do not change as quickly as the increases in disease incidence suggesting a role for changing environmental factors.
Our intestines carry a complex bacterial community (the gut microbiome) that is essential for normal metabolism and, for the normal development and function of the immune system. Using special laboratory rodent strains carrying genetic variations causing T1D, we have shown that their gut microbiomes differ from those of closely related disease-resistant rodents, and that transfer of normal gut bacteria from low-risk into high-risk animals protects them from T1D. Our project will use state of the art genomic and immunological approaches to determine how benign intestinal bacteria can be used to protect from T1D, to understand “diabetes-protective” bacterial products and the changes they induce in the immune system that confers protection.
In addition to our work in rodent models we will determine how variations in the gut microbiome during early childhood affect the development of T1D in a large, multi-national study of children with high genetic risk for the disease. Our goal is a safe, biotic intervention that delays progression of beta cell destruction or prevents diabetes. A therapy that produced these outcomes in even a fraction of high-risk children would confer a highly significant health impact in Canada and around the world.
Lymphoblastic development in acute lymphoblastic leukemia
Leukemias and lymphomas, like all cancers, arise when cells reproduce unrestrainedly due to mutations in genes that control cell division, differentiation, survival or programmed cell death. Our research program is designed to probe the developmental steps and mechanisms of leukemia- and lymphomagenesis in mouse models and in humans. We are working collaboratively within a specialized centre of leukemia research to validate the findings obtained from murine model systems, cell lines and primary human leukemia cells to determine how our findings can improve the diagnosis and prognosis of leukemia.
Our specific areas of interest are: 1) intracellular signalling pathways that govern cell survival, differentiation or death fate decisions in normal and neoplastic lymphoid cells, 2) identification and analysis of the leukemia initiating cell(s), or leukemia stem cells, that initiate and sustain the leukemic clone to understand how genes and molecular pathways operate in leukemic initiation and progression, and 3) how leukemic blasts can survive and expand in the central nervous system (CNS) causing a major clinical complication of leukemia and lymphomas.
The long-term objective of this program is to functionally translate knowledge gained in mouse and cell line model systems to primary human leukemia, to provide evidence to inform future clinical trials.
Therapeutic modulation of SIRPα-CD47
Blood stem cell (BSC) transplantation delivers healthy BSC into the bone marrow of patients whose own BSC have been destroyed by disease, chemotherapy, or radiation treatments, allowing them to produce new, healthy blood cells. However, because transplanted BSC are “foreign” cells, they can be attacked by the patient’s immune system, preventing their survival in the bone marrow. We discovered that one type of destructive immune reaction that prevents BSC from re-growing a healthy blood system is lessened by an interaction between two proteins, one (called CD47) present on transplanted BSC and the other (called SIRPα) on the patient’s immune cells. We have developed a therapy designed to augment this CD47-SIRPα interaction, thereby protecting transplanted BSC from this type of immune destruction. The first goal of this project is to test the safety and effectiveness of this experimental therapy, in order to pave the way for testing in clinical trials. Such a therapy could greatly enhance the use of BSC transplantation to treat leukemia and other cancers.
As in the normal blood system, there are stem cells in acute myeloid leukemia (AML-SC). If AML-SC are not killed by chemotherapy, they are able to re-grow the disease, causing relapse. Like normal BSC, CD47 protein is present on AML-SC. There is experimental evidence that AML-SC may use the interaction between CD47 and SIRPα on the patient’s immune cells to evade immune attack, allowing them to survive and spread in the patient. The second goal of this project is to develop new treatments that block CD47-SIRPα interactions in order to make AML-SC vulnerable to immune attack. Only by killing AML-SC can patients be permanently cured. These new treatments would be used together with standard chemotherapy which is often not very good at killing AML-SC.Canadians.