DICER1 syndrome is a rare, inherited disorder; individuals with a mutation (change) in the DICER1 gene are at increased risk of a variety of cancerous and non-cancerous (benign) tumors. It affects mostly children and young adults. These cancers can be lethal at advanced stages of disease with no biologically-informed treatment strategies available. Despite the discovery of the gene, DICER1, being attributed to cancer development, the translation of this genomic discovery to the bedside to improve cancer care has been hindered by the lack of relevant models to study the disease. My post-doctoral research project will focus on one such aggressive rare cancer, called ovarian Sertoli-Leydig cell tumor. I will use the unique tools/resources such as a large cohort of patient samples and the first-ever mouse model of DICER1 syndrome-associated cancer to understand the biology of this rare ovarian cancer and identify potential druggable candidates for future therapeutic development.
Research Pillar: Biomedical Research
Elucidating how the Sotos Syndrome gene NSD1 controls gene expression during neuronal differentiation.
Each cell has the same genetic information, our DNA. Yet, our body consists of many different cell types (eg. muscle cells, brain cells, etc). To become a specific cell type, our cells have the ability to turn genes in our DNA on or off. This selective control of genes is achieved via “epigenetics”, which means on top (epi-) of our genes (genetics). Epigenetics involves chemical changes to proteins that organize our DNA, which are called histones. Changes to histones are made by epigenetic enzymes. When epigenetic enzymes are defective the wrong changes are made to histones. In turn, the wrong genes are turned on or off, leading to disease. An example of such a disease is Sotos Syndrome, a neurodevelopmental disorder caused by a defect in the epigenetic enzyme NSD1. Exactly how defective NSD1 leads to misguided control of genes is unknown. To examine this, I will use gene editing and delete NSD1 in neuronal precursor cells. Next, I will study the effect of defective NSD1 on histone changes and identify which genes are wrongfully turned on or off in these cells. The results from this study will show how defective NSD1 leads to misguided gene control and can help identify new options for the treatment of Sotos Syndrome.
Using unbiased whole brain methods to understand how impact direction affects the neuropathology of traumatic brain injury in mice
Traumatic Brain Injury (TBI) is a leading cause of death and disability worldwide and often caused by falls, motor vehicle accidents, sports, and violence. Most TBIs are mild (concussion-like) and involve head motion in one or more planes. Although many clinical studies show that complex rotational head motion is associated with worse outcomes, the underlying reasons are unknown. My project aims to fill this gap by determining how head motion during impact relates to changes in levels of injury blood biomarkers and brain pathology in mice. Using our established non-surgical TBI model called CHIMERA (to imitate human TBI), I will deliver impact to the back or side of the head, and measure how the head moves during these impacts using high-speed cameras. I will use cutting edge tissue clearing method to examine brain in 3D and map changes in neuronal activity, axonal and vascular integrity. I will test how these impacts lead to changes in blood biomarkers using clinically relevant tests. Overall, this study will help us understand how impact biomechanics relates to TBI outcomes, which is tremendously important for the future design of helmets and other safety equipment, sport coaching, and concussion rehabilitation.
A chemical biology approach to uncovering modulators of a Parkinson’s disease-linked protein
Enzymes are biological machines which facilitate crucial processes in the human body. A reduction in the function of a given enzyme, sometimes brought about by an alteration or “mutation” to the underlying genetic code, often results in disease. In Parkinson’s disease (PD), a mutation in the GBA1 gene can cause earlier disease onset and rapid motor decline. Furthermore, the enzyme glucocerebrosidase (GCase) that is encoded by GBA1 is less active in PD patients regardless of whether they have a defective GBA1 gene. We hypothesize that GCase is altered or “modulated” by other proteins within the cell. My first goal in this project will be to create improved ways to measure the activity of GCase in live human cells. Previous work has shown that “ratiometric fluorescence sensors” – small molecules which light up when processed by a target enzyme – have high efficacy towards this end. The activity of a large library of existing drug candidates will then be tested for their ability to modulate GCase. Changes measured in GCase activity within cells treated with these drug candidates will help identify these aforementioned unknown “modulators”, thus revealing new insights into the mechanisms of PD and opening new therapeutic approaches.
Development of mutation-robust vaccines and antibodies, and their implications for the evolution of SARS-CoV-2
COVID-19 has caused over 774 million cases and 7.02 million deaths worldwide as of February, 2024. The causative RNA virus, SARS-CoV-2, has the ability to rapidly mutate genetically, and these mutations allow it to swiftly infect with increased efficacy and/or severity. These mutations are of concern because they allow SARS-CoV-2 to evade not only antibodies formed by natural infection or vaccines, but also recombinant antibody therapeutics. With new variants emerging roughly every other month, it will not be long before the current repertoire of antibodies and vaccines against SARS-CoV-2 becomes obsolete. Although it is difficult to predict the mutations in the next variant, it is possible with current technologies to examine potential mutations and the activity of such mutated variants. In this proposal, we will test the robustness of mutation-tolerant de novo vaccines and antibodies against SARS-CoV-2. We also seek to understand how SARS-CoV-2 evolves over time and to decipher the mechanism of antigenic escape from diverse antibodies. This platform can guide us in the design of better therapeutics to combat current and future variants of SARS-CoV-2, and other viruses.
Understanding sex differences in beta-cell resilience to stresses in type 1 diabetes
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.
Structural and Functional Investigation of Neuronal Calcium Channel Modulation
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.
Triggered release of anti-cancer drugs using hybrid lipid nanoparticle technology
Drugs used in cancer treatment, unfortunately, also can harm healthy cells. We’re working on a better way to deliver these drugs directly to cancer cells, minimizing damage to healthy tissues. Imagine tiny particles, like microscopic delivery trucks, that carry cancer drugs. These particles are made from fats and can hold both a cancer-fighting drug, doxorubicin, and special iron particles. What’s unique about these tiny trucks is that they release their drug only when hit by a certain type of radio wave. This means we can target the drug right at the cancer cells, releasing it quickly and precisely. Our first goal is to make these special particles. Then, we’ll test if we can use radio waves to release the drug quickly in lab experiments. Lastly, we hope to show that this method works well in treating cancer in animal studies. Previously, our team has successfully translated scientific research into practical therapies, and we believe this might be yet another example of our achievement in advancing the efficacy of cancer therapy and safety.
Uncovering the role of long non-coding RNA PAN3-AS1 in acute myeloid leukemia
In Canada, Acute Myeloid Leukemia (AML) presents a significant challenge, with only a 30% five-year survival rate and 30% of patients relapsing after treatment. While the genetic mutations in AML’s protein-coding genes are well identified and characterized, the impact of changes in non-coding genes, especially long non-coding RNAs (lncRNAs), remains largely unclear. Our research has identified a specific lncRNA, PAN3-AS1, as a critical factor in leukemia development, with its high expression linked to worse outcomes in AML patients. Our goal is to unravel the molecular functions of PAN3-AS1 in regulating gene expression in AML and to develop targeted therapies against it. We plan to use comprehensive multi-omics analyses to understand PAN3-AS1’s effects and apply innovative drug delivery techniques, such as antisense oligonucleotides (ASOs) and lipid nanoparticles (LNPs), to target PAN3-AS1 in human cells. This work aims to enhance our understanding of lncRNAs in cancer development and spearhead new, effective cancer treatments.
Quantifying navigational impairments in preclinical Alzheimer’s disease
Our brain contains a ‘cognitive map’ of the external world that helps us navigate, and encode/retrieve memories. Dementias such as Alzheimer’s Disease (AD) degenerate these regions, causing well-known memory impairments and much less well-understood navigational impairments. My research program seeks to quantify how navigation is impacted in early AD in rodents and humans.
Young and older human participants will navigate a virtual reality maze. We will quantify how their errors in positioning and navigating scale when the complexity of the task is increased. We will perform similar experiments in rats navigating a physical maze, where we can additionally record neural activity. We will then extend the task to participants diagnosed with preclinical AD, and rodent models of AD. We will characterize the behavioural and neural correlates of early progression of AD, with the goal of finding a metric that is predictive of AD-induced cognitive impairment, and its underlying neural mechanisms.
Over 60,000 British Columbians currently live with dementia. A non-invasive and affordable test such as this will allow clinicians to perform early diagnosis, and start approaches that reduce symptoms and improve quality of life.