Research Location: University of British Columbia - Vancouver Campus

Immune cells can be very effective at killing cancer cells, but tumours have the ability to suppress the immune system. This is why some of the best cancer therapies work by turning the immune system back on. To do this, it is key to understand what controls immune responses in the tumour. In inflammation, it has been shown that neurons can control the immune system. Interestingly, there is evidence that by removing neurons, cancer growth is reduced. We have discovered that when the “heat sensing” TRPV1 neurons are removed in mice, the tumor will grow much slower. We will looked at changes in immune cells using flow cytometry, which allows us to measure over 20 different immune cell types and discovered that these mice may have lower numbers of a rare cell type called ILC2. Next we are trying to understand how neurons are affecting these cells and the tumor growth. Finally, we will design a cell culture system where neurons and mini-cancers will be grown together to see if the tumors are secreting something that changes the expression of genes by neurons. This will lead to the development of novel therapies that activate the immune system by targeting neurons and provide new information on therapeutic avenues for breast cancer.

Light adaptation is the ability of visual system to adjust its performance to the ambient level of illumination. It is fundamentally vital for the normal functioning of the visual system. During the normal cycle of day and night, the illumination of the earth’s surface varies over 11 orders of magnitude. The daily cycle of sensitivity adjustment is managed by switching between rod and cone pathways of retina. These pathways involve retinal guanylyl cyclase (retGC), an enzyme encoded by the GUCY2D gene expressed in rod and cone photoreceptors. In the light-induced signal cascade, retGC restores cGMP levels in the dark in a calcium-dependent manner. Mutations in GUCY2D are associated with recessive Leber congenital amaurosis-1 (LCA1) as well as dominant and recessive forms of cone-rod dystrophy (CORD). Presently, the molecular structure of retinal GC has not been determined; thus, its mechanism, interaction with other regulators, and identity of crucial residues conferring the activity of this enzyme have been elusive. We aim to fill this gap in our knowledge by determining the molecular structure of retGC. This information will enhance our understanding of the role of retGC in photoreceptors and diseases.

Type 1 diabetes (T1D) involves the loss of insulin-secreting beta-cells, the main cell type in the pancreatic islets. A special feature of beta-cells is that they must make large quantities of insulin protein, which is very demanding and leaves them vulnerable to stress. Stressed islets are less functional and may die. Islets from females appear more resilient than islets from males to stresses relating to insulin production. However, we lack knowledge on how female islet cells achieve this, and preclinical research rarely studies both sexes. This project will characterise the mechanisms that occur in male and female islets in response to T1D-related stresses. We will generate and analyse large datasets to identify key stress response events in mouse and human donor islets. Results will be presented at scientific conferences. By understanding these mechanisms, we will likely identify therapeutic targets that can lead to future drug and cell therapies for T1D. A focus on sex differences is also key to ensuring appropriate research translation to a wider population. Finally, a fundamental understanding of sex differences in protein synthesis has implications for studies in other cells and organs, as all cells need to make protein.

Cells contain highly complex protein structures that allow signals to be relayed from the outside environment using signaling receptors to proteins inside of the cell. One mechanism involves assembling protein complexes across different cell layers linked by proteins such as junctophilins (JPH). JPH proteins are found in the brain and muscles and work by interacting with receptors on the outer layer while simultaneously interacting with proteins on inner cellular structures such as the endoplasmic reticulum (ER). Thus, JPH places the outer layer of the cell and the ER in proximity allowing for a direct exchange of signals. This is essential for muscle contraction and memory and is linked to human genetic diseases. However, the interaction sites between these JPH proteins and their effect on receptors, such as voltage-receptor channels (Cav2), remain elusive. Here, we want to use X-ray crystallography and electron microscopy to solve the protein structure of JPH and find how it interacts and regulates Ca¬v receptors. This work will provide insights into JPHs’ molecular structure, cellular function and role in genetic diseases. The JPH-Cav molecular complex will serve as a resource for future mechanistic studies and drug designs.