Relevant Thesis-Based Degree Programs
Affiliations to Research Centres, Institutes & Clusters
Immunometabolism and gut health
Complete these steps before you reach out to a faculty member!
- Familiarize yourself with program requirements. You want to learn as much as possible from the information available to you before you reach out to a faculty member. Be sure to visit the graduate degree program listing and program-specific websites.
- Check whether the program requires you to seek commitment from a supervisor prior to submitting an application. For some programs this is an essential step while others match successful applicants with faculty members within the first year of study. This is either indicated in the program profile under "Admission Information & Requirements" - "Prepare Application" - "Supervision" or on the program website.
- Identify specific faculty members who are conducting research in your specific area of interest.
- Establish that your research interests align with the faculty member’s research interests.
- Read up on the faculty members in the program and the research being conducted in the department.
- Familiarize yourself with their work, read their recent publications and past theses/dissertations that they supervised. Be certain that their research is indeed what you are hoping to study.
- Compose an error-free and grammatically correct email addressed to your specifically targeted faculty member, and remember to use their correct titles.
- Do not send non-specific, mass emails to everyone in the department hoping for a match.
- Address the faculty members by name. Your contact should be genuine rather than generic.
- Include a brief outline of your academic background, why you are interested in working with the faculty member, and what experience you could bring to the department. The supervision enquiry form guides you with targeted questions. Ensure to craft compelling answers to these questions.
- Highlight your achievements and why you are a top student. Faculty members receive dozens of requests from prospective students and you may have less than 30 seconds to pique someone’s interest.
- Demonstrate that you are familiar with their research:
- Convey the specific ways you are a good fit for the program.
- Convey the specific ways the program/lab/faculty member is a good fit for the research you are interested in/already conducting.
- Be enthusiastic, but don’t overdo it.
G+PS regularly provides virtual sessions that focus on admission requirements and procedures and tips how to improve your application.
ADVICE AND INSIGHTS FROM UBC FACULTY ON REACHING OUT TO SUPERVISORS
These videos contain some general advice from faculty across UBC on finding and reaching out to a potential thesis supervisor.
Graduate Student Supervision
Doctoral Student Supervision
Dissertations completed in 2010 or later are listed below. Please note that there is a 6-12 month delay to add the latest dissertations.
Macrophages initiate the immune response and contribute to the inflammation that characterizes many diseases. Macrophages play an equally important role in turning off the inflammatory response, by producing the anti-inflammatory cytokine IL-10. Intravenous immunoglobulin (IVIg) is a drug made up of pooled polyclonal IgGs, which is used to treat immune-mediated diseases. However, its mechanism of action is not completely understood. We found that IVIg induced high production of IL-10 and low production of pro-inflammatory cytokines by murine bone marrow-derived macrophages (BMDMs) treated with lipopolysaccharide (LPS), an inflammatory stimulus. MAPKs, Erk5, Erk1/2, and p38, were activated by co-stimulation with IVIg and LPS and their activation was required for IL-10 production. In vivo, murine peritoneal macrophages also produced high levels of IL-10 and low levels of IL-12/23p40 when treated with IVIg + LPS. Inflammatory bowel disease (IBD) is characterized by chronic inflammation of the intestine. IVIg-treated macrophages or IVIg treatment ameliorated intestinal inflammation in mice during dextran sulfate sodium (DSS)-induced colitis. Moreover, IVIg-induced macrophage IL-10 production was required for IVIg-mediated protection. In human monocytes, IVIg also increased IL-10 production and reduced pro-inflammatory cytokine production in response to LPS. IVIg-induced IL-10 production required the FcγRI and FcγRIIB as well as activation of MAPKs, ERK1/2 and p38. An FcγRIIA gene variant predisposes people to develop immune-mediated diseases, such as IBD, and has been linked to a failure to respond to antibody therapy. The FcγRIIA disease risk variant changes this receptor from a low to a high affinity receptor. My results demonstrated that IVIg-induced anti-inflammatory responses were compromised in monocytes from people with the FcγRIIA risk variant. Together, these results describe a novel mechanism of action for IVIg, the induction of anti-inflammatory, IL-10 producing macrophages. IVIg may provide an effective therapeutic option to treat people with IBD. However, induction of this anti-inflammatory activation state may be impaired in monocytes from people with the disease-associated FcγRIIA gene variant. In summary, understanding IVIg’s mechanism of action may inform new applications, prompt development of new therapeutic strategies for immune-mediated diseases, and identify individuals for whom IVIg will be most effective.
Combined immunodeficiency caused by a homozygous mutation in the mucosa associated lymphoid tissue 1 (MALT1) gene is associated with severe inflammation along the gastrointestinal tract and osteoporosis, which were corrected by hematopoietic stem cell transplant (HSCT). The consequences of Malt1 deficiency have largely been attributed to its role in lymphocytes, but Malt1 is also expressed in myeloid cells. The effect of Malt1 deficiency in macrophages and osteoclasts and their contribution to inflammatory bowel disease (IBD) and osteoporosis respectively have not been investigated. My objectives were to determine the contribution of Malt1-/- macrophages to dextran sodium sulfate (DSS)-induced colitis in mice and to assess the effect of innate immune stimuli on Malt1-/- macrophage inflammatory responses. I also studied the level of Malt1 expression during intestinal inflammation in humans and mice. I next asked whether Malt1-deficient mice develop an osteoporosis-like phenotype and whether it is caused by the effect of Malt1 deficiency on osteoclast differentiation and/or activity. I found that Malt1 deficiency exacerbates DSS-induced colitis in mice, and that macrophages and IL-1 signaling contribute to pathology in Malt1-/- mice. Innate immune stimuli induced Malt1 protein levels in murine macrophages in vitro. However, intestinal inflammation did not have any effect on Malt1 expression in humans and mice in vivo. I also found that adult Malt1-deficient mice have lower bone volume, and Malt1 expression and activity is induced by receptor activator of nuclear factor κB ligand (RANKL) in preosteoclasts. Malt1 deficiency did not impact osteoclast differentiation or activity in vitro but their number was higher in Malt1-/- mice in vivo. Inhibition of Malt1 activity in macrophages after activation by inflammatory stimuli induced macrophage colony-stimulating factor (MCSF) production, required for osteoclastogenesis, and decreased OPG production, an endogenous inhibitor of osteoclastogenesis, which was also lower in Malt1-/- mice serum. Taken together, these data demonstrate that Malt1-/- mice are more susceptible to DSS-induced colitis through higher IL-1 production by Malt1-/- macrophages and these mice develop an osteoporotic phenotype with increased osteoclastogenesis in vivo, which is caused by inflammation rather than a cell-intrinsic effect of Malt1 deficiency in osteoclasts.
Crohn`s disease (CD) is a polygenic immune-mediated disease of the gastrointestinal tract characterized by chronic inflammation. The SH2-domain-containing inositol polyphosphate 5΄phosphatase (SHIP) is a hematopoietic-specific negative regulator of inflammatory cytokine production and plays an important role in regulating immune homeostasis. Using the SHIP deficient mouse model of intestinal inflammation, we found that IL-1β is increased in SHIP-/- mouse macrophages due to increased class I PI3K p110α activity. Macrophage depletion or treatment with an IL-1 receptor antagonist reduced development of intestinal inflammation in SHIP-/- mice. To interrogate if SHIP is dysregulated in people with ileal CD, we demonstrate that subjects with ileal CD have reduced SHIP mRNA expression and enzymatic activity at sites of inflammation and in PBMCs, compared to control subjects. A single nucleotide polymorphism (SNP) in the gene encoding ATG16L1 (T300A) causes an autophagy defect and is associated with increased IL-1β production and susceptibility to CD. In all tissues from our patient cohort and in PBMCs from a second healthy control cohort, subjects, who were homozygous for the CD-associated ATG16L1 T300A encoding gene variant, had reduced SHIP mRNA expression and enzymatic activity, which correlated with increased IL-1β production. In addition, starvation-induced autophagy increased SHIP protein levels, which were reduced in the presence of the ATG16L1 CD-associated risk allele. Examining the effects of additional autophagy and CD-related gene variants, which may affect SHIP mRNA expression and enzymatic activity, on IL-1β production in PBMCs from a cohort of healthy control subjects, we found that the NOD2 rs2066844 and the XBP-1 rs35873774 gene variants were associated with increased IL-1β production in response to specific PAMPs.Collectively, these data identify SHIP up-regulation as a novel mechanism by which autophagy regulates IL-1β production and intestinal autoinflammation. Our findings also identify a subgroup of CD patients that could be amenable to treatment with therapy that targets IL-1β.
Inflammatory bowel disease (IBD) is an idiopathic disease characterized by chronic intestinalinflammation and ulceration. Canada has the highest incidence of IBD in the world with 1 in150 people affected. While treatment options target symptoms and attempt to dampen downinflammation, an increasing population of patients is refractory to current therapeuticoptions. Macrophages are heterogeneous in their functions and while it is clear thatinflammatory macrophages contribute to inflammation in IBD, multiple lines of evidencesuggest that alternatively activated macrophages may offer protection during intestinalinflammation. In vivo SHIP deficient mouse macrophages are alternatively activated soSHIP deficient mice provide a unique genetic model of alternative macrophage activation.Using the dextran sodium sulfate (DSS)-induced model of colitis, I found that SHIP-/- miceare protected during induced intestinal inflammation, the protection is macrophage mediated,and can be conferred to a susceptible host. To determine how SHIP contributes to alternativeactivation of macrophages, I demonstrate that SHIP-deficient murine macrophages are moresensitive to IL-4-mediated skewing to an alternatively activated phenotype. Moreover, SHIPlevels are reduced in alternatively activated macrophages and this is required for alternativeactivation because it is dependent on PI3K activity. Arginase (ArgI) induction is specificallydependent on the PI3Kp110δ isoform of class IA PI3K. As such, mice deficient inPI3Kp110δ catalytic subunit activity have increased clinical disease activity and histologicaldamage during DSS-induced colitis. Colitis severity correlates with reduced numbers ofArgI+ M2 macrophages in the colon, increased nitric oxide production, and is macrophagedependent.Importantly, adoptive transfer of IL-4-treated macrophages from wild type mice,but not from PI3Kp110δ deficient mice, protects mice during DSS-induced colitis. Protection is lost when mice are treated with inhibitors that block arginase activity showing that ArgI activity is required for M2 macrophage-mediated protection from intestinal inflammation. These findings identify SHIP and the PI3K pathway as critical regulators of alternative macrophage activation and as potential targets for manipulation in IBD. In addition, adoptive transfer of alternatively activated macrophages to patients with IBD also offers a promising, new strategy for treatment that may be particularly useful in patients who are refractory to conventional therapies.
Master's Student Supervision
Theses completed in 2010 or later are listed below. Please note that there is a 6-12 month delay to add the latest theses.
Inflammatory bowel disease (IBD), encompassing Crohn’s Disease (CD) and ulcerative colitis, is characterized by gastrointestinal inflammation. Inflammation can be chronic, relapsing and remitting, or progressive, and accompanied by symptoms of pain, nausea, and diarrhea. Treatment in children or people with mild-to-moderate IBD follows a step-up approach to therapy, beginning with NSAIDs before moving to steroids, immunomodulators, and finally biologics. Though corticosteroids reduce inflammation, their use is limited by adverse dose-dependent systemic effects which include, but are not limited to immunosuppression, mood changes, and, in children, negative effects on growth and development. We present the use of a drug delivery system, termed “GlycoCage” in a SHIP-deficient (SHIP-/-) mouse model of CD-like ileitis, conjugated to the corticosteroid, dexamethasone (DEX). The GlycoCage renders active corticosteroids inactive until they are released from the GlycoCage. “De-caging” relies on commensal bacteria which produce enzymes, called xyloglucanases, to digest the GlycoCage and release active corticosteroid near the site of disease. I found that xyloglucanase activity along the gastrointestinal tract of SHIP-/- mice is inducible with 2% xyloglucan supplementation in the diet essentially priming the microbiome to release GlycoCaged therapies. I also found that the CD-like ileitis in SHIP-/- mice can be treated with GlycoCaged DEX at a minimum effective dose 10-fold lower than free DEX. Specifically, I observed doses of GlycoCaged DEX 10-fold lower than that of free DEX resulted in a reduction of gross ileal pathology, histopathology, and inflammatory cytokine production in the distal ileum of SHIP-/- mice. Additionally, I observed off-target effects on the lungs and mesenteric lymph nodes when mice were treated with free DEX. These off-target effects were eliminated when mice were treated with GlycoCaged DEX. Together my data suggests GlycoCaged DEX is more efficacious and has reduced off-target effects when compared to free DEX, supporting its potential to improve current corticosteroid treatments for IBD. This work provides the foundation for analyzing the GlycoCage in murine models of intestinal inflammation and supports further research to explore its applications for human use.
Inflammatory bowel disease (IBD) is characterized by inflammation along the gastrointestinal tract, which may develop from disruptions in mucosal homeostasis. Intestinal epithelial cells are central in maintaining homeostasis by recognizing and responding to extracellular signals. One of these cell types, tuft cells, has been proposed to have a role in secretion, absorption, and/or reception. However, their role in the intestine remains understudied. We found that tuft cells express SH2 domain-containing inositol 5'-phosphatase (SHIP), which is thought to be hematopoietic-specific. SHIP is a negative regulator of the PI3-kinase pathway, so SHIP deficiency increases PI3K-mediated cell growth, proliferation, and activation. Tuft cells secrete IL-25, which activates group 2 innate lymphoid cells (ILC2s), inducing type 2 immune responses that can promote inflammation and tissue repair. Tuft cells also express cyclooxygenase (COX)1 and COX2, which produce prostaglandins that regulate inflammation and repair. I hypothesized that SHIP deficiency in tuft cells increases their activity, promoting inflammation and/or healing via activation of type 2 immunity and prostaglandin synthesis. We created a mouse deficient in SHIP only in intestinal tuft cells to examine tuft cell functions in DSS-induced colitis, a mouse model of colonic inflammation. I found that mice with SHIP-deficient tuft cells have exacerbated DSS-induced colitis that is accompanied by elevated IL-25 concentrations and reduced COX activity. IL-5 and IL-13 concentrations were not increased, suggesting that these type 2 cytokines did not worsen disease and the tuft cell-ILC2 circuit may not function in the colon. Pro-inflammatory mediators, eosinophils, IL-1β, IL-6, and TNF-α, did not appear to exacerbate disease. Rather, my results suggest that endogenous IL-25 plays a pro-inflammatory role, whereas COX is protective in DSS-induced colitis. I evaluated the potential protective function of COX during recovery from DSS-induced colitis. I found that mice with SHIP-deficient tuft cells have increased disease activity early in recovery and may have some histological features that are consistent with increased type 2-mediated healing. Investigating the role of tuft cell-derived IL-25 and COX in DSS-induced colitis and recovery may provide insight into the biological processes that occur in the development of intestinal inflammation that is pertinent to IBD.
Inflammatory bowel disease (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC), is characterized by intestinal inflammation. Intestinal epithelial cells play a critical role in mucosal homeostasis and dysregulation of pro-inflammatory epithelial cell function could lead to the intestinal inflammation that characterizes IBD. However, we do not know the events that initiate inflammation or the cell types involved. One type of cell that may play a role is the tuft cell. Tuft cells are the only epithelial cells in the uninflamed intestine that express cyclooxygenase (COX)1 and COX2, the rate-limiting enzymes required for production of prostaglandins, like PGE2 and PGD2 which play important roles in immunity. In our research investigating the lipid phosphatase SHIP, it was discovered that tuft cells express SHIP. SHIP deficiency leads to increased PI3-kinase activity in cells resulting in increased cell proliferation, reduced apoptosis, and increased cell activation. SHIP expression is currently believed to be restricted to hematopoietic cells. However, using bone marrow transplantation, our laboratory found that tuft cells were not radiosensitive, suggesting that they are not bone-marrow derived and are not hematopoietic in origin.In addition, SHIP-deficient mice develop spontaneous Crohn’s disease-like intestinal inflammation. The onset of inflammation coincides with the developmental appearance of tuft cells. In wild type mice, tuft cells are found in the lung and ileum, both locations where SHIP-deficient mice develop spontaneous inflammation, and I found that tuft cell numbers were increased 6-fold in the inflamed ileum of SHIP-deficient mice. Based on this, I hypothesized that SHIP-deficient tuft cells may initiate or contribute to inflammation in the SHIP-deficient mouse. I found that SHIP-deficient mice had more COX1 positive cells in the ileum, more COX activity, and more PGD2 and PGE2 in full thickness ileal tissue homogenates, compared to their wild-type littermates. Finally, prophylactic inhibition of COX activity with piroxicam reduced the development of intestinal inflammation in SHIP-deficient mice whereas therapeutic treatment had little effect. This suggests that tuft cells may be critical in the initiation of spontaneous intestinal inflammation in SHIP-deficient mice and help elucidate some of the basic biology involved in the inflammation present in patients with CD.
Inflammatory bowel disease, encompassing both ulcerative colitis and Crohn’s disease, is characterized by chronic, relapsing-remitting gastrointestinal inflammation of unknown etiology. SHIP deficient mice develop fully penetrant, spontaneous ileitis at 6 weeks of age, and thus offer a tractable model of Crohn’s disease-like inflammation. Since disruptions to the microbiome are implicated in the pathogenesis of Crohn’s disease, we conducted a 16S rRNA gene survey of the ileum, cecum, colon, and stool contents of SHIP+/+ and SHIP-/- mice. We predicted that diversity and compositional changes would occur after, and possibly prior to, the onset of overt disease. No differences were found in alpha diversity, but significant changes in beta diversity, specific commensal populations, and the inferred metagenome were observed in the ileal compartment of SHIP deficient mice after the onset of overt disease. Specifically, reductions in the Bacteroidales taxa, Muribaculum intestinale, and an expansion in Lactobacillus were most notable. In contrast, expansions to bacterial taxa previously associated with inflammation, including Bacteroides, Parabacteroides, and Prevotella were observed in the ilea of SHIP deficient mice prior to the onset of overt disease. Thus, our findings indicate that SHIP is involved in maintaining ileal microbial homeostasis. These results have broader implications for humans, since reduced SHIP protein levels have been reported in people with Crohn’s disease.
Crohn’s disease (CD) is an immune-mediated disease characterized by inflammation along the gastrointestinal tract. One in 3 people with CD will develop intestinal fibrosis requiring surgery within 10 years of diagnosis. Despite that, there are no treatments that target intestinal fibrosis directly. Our laboratory reported that mice deficient in the Src homology 2 domain-containing inositol polyphosphate 5´-phosphatase (SHIP-/-) develop spontaneous CD-like intestinal inflammation with arginase-dependent fibrosis. We also reported that increased arginase I activity in SHIP-/- macrophages was dependent on increased Class IA phosphatidylinositol 3-kinase (PI3K) p110δ activity. Based on this, we hypothesized that SHIP-/- mice develop fibrosis due to increased PI3Kp110δ activity. SHIP-/- mice were crossed with mice deficient in PI3Kp110δ activity (PI3Kp110δDA/DA). SHIP-/- PI3Kp110δDA/DA mice have reduced intestinal fibrosis compared to their SHIP-/- littermates including: reduced muscle thickening, vimentin+ mesenchymal cells, collagen deposition, arginase activity, and IL-4 levels. SHIP-/- mice were also treated with a PI3Kp110δ isoform-specific inhibitor, IC87114. Pharmacological inhibition of PI3Kp110δ activity also reduced the above parameters that are associated with intestinal fibrosis in SHIP-/- mice. Surprisingly, PI3Kp110δ deficiency or inhibition also reduced ileal inflammation and IL-1β production in the SHIP-/- ileum suggesting that PI3Kp110δ, and/or fibrosis itself, may contribute directly to inflammation. Our data suggest that SHIP-/- mice develop intestinal fibrosis that is driven by PI3Kp110δ activity. Moreover, targeting PI3Kp110δ activity may be an effective strategy to reduce intestinal fibrosis in people with CD. Importantly, there are PI3Kp110δ isoform-specific inhibitors already licensed for use in people with certain leukemias and lymphomas, so this research may be rapidly translatable into an effective therapy for intestinal fibrosis in people with CD.