Plants are endowed with biological catalysts (enzymes) that make natural drugs used to treat various human illnesses. Among these, the Chinese happy tree (Camptotheca acuminata) produces the anticancer drug camptothecin. Although camptothecin is readily convertible to the more potent drugs topotecan (Hycamtin) and irinotecan (Camptosar), this requires chemical synthesis steps which rely on toxic chemicals and petroleum-based resources.
Our research program aims at developing multidisciplinary approaches to discover and modify happy tree’s enzymes that facilitate the production topotecan, irinotecan and new camptothecin-derived analogues. We aim to rapidly generate 25-50 camptothecin-derived analogues by biotechnological means and test these compounds using in vitro and cellular assays to assess potential anti-cancer activity.
Our biosynthetic approach will allow us to explore the untapped medicinal potentials of a whole host of novel camptothecin-related chemicals in addition to topotecan and irinotecan. Long-term efforts, also ongoing in our laboratory, will focus on synthetic biology approaches to scale up production of compounds that show promising bioactivity.
Morphogenesis is the process by which an organism develops its shape. Defects in this process are linked to several diseases and defects such as cancers, heart defects at birth, and cleft lip/palate. The study of morphogenesis is critical to understanding these conditions and identifying new treatments.
Cytokinesis, a critical step of cell division that separates a dividing cell into two daughter cells, plays a major role in morphogenesis. It not only contributes to the multiplication of cells but also their arrangement within their space, giving rise to different structures. It does this by controlling the position and orientation of division—a process called symmetry-breaking. The coordinated flow of a gel layer on the cell surface—cortical flow—is a driving force of symmetry-breaking.
The goal of this research is to understand the mechanisms that control cortical flow during morphogenesis. Using genetic methods and advanced microscopy in living cells, we have found new molecular pathways that control the speed and direction of cortical flow.
By shedding further light on these mechanisms our research will identify molecules and pathways which can be used to develop new medicines to prevent and cure morphogenesis defects.
Fear memory, like that occurring in post-traumatic stress disorder, imposes pronounced health and financial burdens. Our laboratory seeks to understand and therapeutically disrupt the neurobiological elements of fear memory.
To do this, we take a multidisciplinary approach that combines cutting-edge experimental and computational techniques. To begin, in mice that have obtained fear memory in a laboratory setting, we measure the expression of every gene in the mouse genome for thousands of individual brain neurons. From these Big Data, we identify genes and neuron types that participate in fear memory. Using genetic and pharmacologic approaches, we manipulate these genes and neuron types with the aim of disrupting fear memory in a safe, acute, and precise way.
The results of this research will provide a comprehensive understanding of the basic biology of memory, help to innovate novel targets and approaches for disrupting fear memory, and generate a framework with which other anxiety and memory disorders may be interpreted. In the long term, we aim for these results to guide the generation of new therapeutic approaches for preventing traumatic fear memory in humans.
Cancer is a disease of the genome that disrupt the cells’ key functions and make them grow uncontrollably. DNA sequencing projects have led us to discover that cancer cells involve many genetic changes and that even in a single tumour, there are often multiple cancer cell populations that each carry their own mutations.
Understanding this collection of mutations is important because we need to select therapies that kill all of the cancer cells, not just some of them. Unfortunately, existing computer programs for analyzing “normal” human genome data generated by genome sequencing technologies are limited in scope because they cannot fully characterize all the mutations present in the individual cells of a tumour tissue.
Ideally, researchers would like to monitor how the genomes of cancer cells mutate over time, and how cancer cells travel through the blood stream or the urinary tract and colonize other tissues, forming metastatic tumours. The new liquid biopsy technology has made it possible to capture tumour DNA circulating in the blood stream and to sequence it, however analyzing such data and identifying the spectrum of mutations in an individual patient will require new mathematical and computational approaches.
Brain disorders are among the most significant health problems of modern day with enormous medical, social and economic burdens in British Columbia, Canada and globally. There is a substantial gap between the burden of brain disorders and the resources available to treat them. Neurodevelopmental disorders are particularly devastating, placing a heavy emotional and economic burden on children and their families. A major challenge in tackling these disorders is the inability to obtain and study brain cells directly. New technologies which allow stem cells to be transformed into brain cells are starting to help overcome this hurdle.
By studying brain cells derived from human stem cells, Dr. Pouladi aims to
- understand how brain disorders develop and
- to identify new ways to treat them. A major focus of his studies are monogenic neurological disorders and in particular fragile X syndrome (FXS). FXS is the most common inherited form of intellectual disability and remains without effective treatments options.
The stem cell-based discovery platform established and knowledge gained as part of Dr. Pouladi's program have the potential to advance therapeutic development for not only FXS, but also other neurodevelopmental disorders.
Cells in our body are constantly engaged in physical interactions. They stick together, squeeze through each other, and each possesses a primitive sense of touch. These physical interactions are crucial in processes that control how we grew from a single cell into a complex organism and how they function. In diseases from cancer to neurodegeneration to chronic inflammation, these mechanical regulatory mechanisms are interrupted or impaired, causing cells to lose control and wreak havoc in our body.
The research proposed here aims to understand the changes to mechanical interactions in diseases down to the molecular scale. To do so, we need to develop tiny molecular tools that will allow us to look at these mechanical interactions through a microscope and control them with drugs.
We will build these tools using the latest DNA nanotechnology, which gives us predictable control over the shape and function of these molecules. We will apply these tools to understand how cancer metastasize to a new place in the body and how neurons break connections in neurodegeneration. This will help us identify drug targets towards a cure to two major diseases with high impact to the health of people in our society.
Human cells are fascinating and complex: they reproduce, break down food to create energy and communicate with each other. The ‘skin’ of the cell, the cell membrane, plays a crucial role in choreographing interactions between a cell and the outside environment, for example by allowing or prohibiting the access of drugs from the cell exterior to the cell interior.
I design and build lab-on-a-chip devices, which are plastic chips the size of a postage stamp inside of which I can manipulate tiny amounts of liquids. I use these lab-on-a-chip devices to create artificial cells to be able to study how the cell membrane regulates access to the cell interior. Human cell membranes have lots of different components that are used to transport drugs into and out of the cell.
Since the cell membrane is complex, we do not always know exactly which component is interacting with the drug molecule, and what effect it has. The cost of developing a new drug is around 2.6 billion USD and a significant proportion of drug candidates fail because we cannot predict how they interact with cells.
My research will help design drugs that can interact with cells more efficiently, so that they can get inside the cell in order to work properly.
Each time SARS-CoV-2 is transmitted from one host to the next, a small random number of point mutations are acquired. These mutations can be used to infer the branching structure of the evolving viruses, which is called a viral phylogenetic tree. Phylogenetic trees inferred from viral sequence data can provide much insight into the dynamics of an epidemic, this is the focus of an area of research called phylodynamics.
However, for this sequencing data to be a useful part of the non-pharmaceutical COVID response, important computation improvements are needed in current phylodynamic software tools, as the computational cost of phylodynamic inference can be in the order of days or weeks. This project aims at applying recent advances to enable these models to be run in real time.
Introduction: Colorectal cancer (CRC) is the second most common cancer. Once metastatic, patients are generally incurable and receive treatment to prolong survival. Immunotherapies use a patient's immune system to attack their cancer. These treatments are effective in CRC patients with microsatellite instability (MSI). Unfortunately, 95% of patients lack MSI and are called microsatellite stable (MSS). This group usually doesn't respond to immunotherapy and we need to explore why.
Specific Aims:
We aim to identify:
- why some MSS patients benefit from immunotherapy, and
- what can we target to activate immune cells in patients who don't respond to immunotherapy.
Methods: We will investigate how the immune system and tumors interact in patients from two clinical trials. These trials evaluated immunotherapy in MSS CRC. Blood and tumor samples from these trials will be tested to identify features that predict response. These results will then guide the creation of new clinical trials with immunotherapy for CRC using our findings.
Significance: Immunotherapy does not work for the 95% of CRC patients who are MSS. We will identify how to activate the immune system in CRC patients with MSS so they too can benefit from immunotherapy.
Recent work from our laboratory has shown that the brain capillaries routinely get 'stuck,' clogged by cells and debris even under healthy conditions. Most of these clogged capillaries clear within seconds to minutes, however, some can remain stuck for much longer. We also reported that about one third of these clogged capillaries were eliminated from the blood vessel network and never get replaced. Importantly, there are certain conditions which can increase the risk of clogged blood vessels in the brain such as diabetes. However, we still do not have a good mechanistic understanding of how these capillary obstructions can be cleared, or even what impact they have on brain function.
In this study, we will characterize capillary obstruction and pruning rates in healthy and diabetic mice brain. Next, we will focus on devising new strategies to enhance the clearance of capillary obstructions. At various time points, the mouse brain will be imaged to assess obstruction clearance and capillary elimination rates. These aims will provide new insights into microcirculatory changes that occur in healthy and diabetic brains, as well as a mechanistic understanding of how capillary obstructions can be cleared.
