"Drawing Maps of Molecular Trafficking"
The human body is made of trillions of cells, and they are extremely organised to selectively transport the "right" molecules to the "right" destinations. A functional transport system of molecules underlies fundamental aspects of life, and it is essential for human health. Problems in the molecular transport system could lead to major health issues. Also, the molecular transport system is responsible to move drugs to diseased organs for effective treatments for all diseases. However, our understanding of how molecules are transported in biological systems is rudimentary. Our lab aims to address this fundamental aspect of life by “drawing maps” of molecular trafficking in the biological system using multidisciplinary technologies, molecule by molecule. Our goal with “drawing” the molecular transport maps is to improve human health by revealing (1) how molecules move in the molecular transport system to support normal health; (2) how “traffic jams” in the transport system cause human diseases; and (3) how to hijack the transport system to move specific molecules (e.g., drugs) to diseased cells for treatments. Our lab plans to achieve this goal through research projects in three streams: Technology, Science and Engineering.
Key questions in the lab:
1. How to better trace nutrients and therapeutics in cells and tissues?
2. How are nutritional molecules transported in biological systems in health and diseases?
3. How are therapeutics, particularly RNA-targeted drugs, transported in healthy and diseased tissues?
4. How to exploit differences of nutrient transport in health and diseases for disease diagnosis and disease progression monitoring?
5. How to hijack the molecular transport system to design better therapeutics?
Technology: new biological imaging approaches to study molecular trafficking and metabolism
In the past few years, we have established reliable protocols to combine NanoSIMS analysis with other advanced microscopy techniques to obtain multimodal information from the exact same sample—ranging from molecules, single cells and tissue sections. These innovative technologies have been an engine of discovery, which have allowed us to visualise important biological processes, as well as to formulate attractive hypotheses for future studies. In this stream, we plan to develop innovative analytical workflow and imaging probes assisted by artificial intelligence combining multimodal techniques, including mass spectrometry, advanced imaging, and stable isotope tracing to comprehensively characterise molecular trafficking and metabolism at single-cell level in health and diseases.
(1) Lipid transport in health and diseases
Taking advantage of novel technologies, our lab have visualised the transport of lipolysis products in normal tissues and tumours, and studied the mechanisms that enable fatty acids to cross glioblastoma capillary endothelial cells. We also discovered the release of cholesterol-rich particles from macrophage filopodia and lamellipodia during their movement. While our progress in visualising lipid transport has been gratifying, some of the basic mechanisms for lipid transport in cells and tissues are still unclear. We plan to further define, using advanced imaging technologies as well as genetic and biochemistry approaches, mechanisms of lipid transport and metabolism.
(2) Transport mechanisms of therapeutics and their carriers
This program aims to improve our fundamental understanding of the transport and delivery of multiple classes of therapeutics (nucleic acid-based therapeutics, antibiotics, metal-complex anticancer drugs, antibodies, and nanomedicines) in cells and tissues. We have recently demonstrated the use of correlative light, electron, and ion microscopy (CLEIM) to study subcellular interactions between therapeutics and cells; and now we are capable of defining drug subcellular distributions and drug activities in the exact same cells. In this program, we plan to define the mechanisms of transport of therapeutics, potential targeting ligands and drug carriers, across biological barriers in cells and tissues.
Engineering: diagnosis and treatment of human diseases targeting molecular trafficking and metabolism
Our lab is exploring bioengineering opportunities in the diagnosis and treatment of human diseases based on our fundamental discoveries on molecular trafficking and metabolism. This stream firstly exploits the distinct contrast in lipid transport between the normal tissues and diseased tissues to develop novel probes for clinical imaging with better imaging properties and greater specificity. Our work will hopefully provide an improved method for monitoring the responses to treatment and designing new strategies for diagnosis and treatment for human diseases. The other program in this stream is to explore precision molecular delivery. Our studies on lipid and drug trafficking have provided and will continue to provide important insights into the mechanisms of the trafficking of these molecules, as well as how targeted ligands help these molecules move across cellular and membrane barriers to reach subcellular sites of action. We will explore possible ways to hijack these mechanisms to deliver nutritional or pharmaceutical molecules into specific tissues, cells and subcellular compartments.