Project Reference No. : C1020-19E
Project Title : High-Resolution Antenna Measurement System with Robotic Arms for Millimeter-wave Frequencies
Project Coordinator : Dr. Hang WONG
University : City University of Hong Kong
Layman Summary
Research team in this project will work together to build up a world-class measurement facility which is a high-resolution antenna measurement system for millimeter and terahertz research at the frequency range from 100 GHz to 0.5 THz. This system will support research and development activities in both academia and industry, paving the way for innovations in 6G and beyond. It is confident that the new facility will promote the high-frequency electronic developments to a new level of excellence, contributing to elevating Hong Kong an international hub for innovation.
Project Reference No. : C4033-19E
Project Title : The First Integrated State-of-the-Art Sample Preparation System for Cryo-Electron Microscopy/Tomography Analysis to Promote Advanced Cellular and Structural Biology Research in Hong Kong
Project Coordinator : Professor JIANG Liwen
University : The Chinese University of Hong Kong
Layman Summary
Cryo-electron tomography (cryo-ET) is the imaging technique of choice for visualizing the native three-dimensional (3D) architecture of biological macromolecules, subcellular structures and organelles in their most natural environment at molecular resolution.
The recently introduced cryo-focused ion beam microscopy (cryo-FIB) milling has become the preferred method for producing thin, artefact-free lamella through state-of-the-art fabrication technology suitable for high-resolution cryo-ET. Furthermore, the development of the integrative cryo-correlative light and electron microscopy (cryo-CLEM) technique has allowed the precise identification of small targets within the cell for cryo-FIB milling and subsequent cryo-ET analysis.
In this project, we aim to establish a complete sample preparation system (e.g. cryo-FIB and cryo-CLEM) to maximize the applications of our existing Cryo-EM/ET platforms to promote advanced cellular and structural biology research as well as collaborative research and research excellence in Hong Kong.
Project Reference No. : C5033-19E
Project Title : An Ultra-speed Mass Spectrometer for High-throughput Omics Studies
Project Coordinator : Dr Zhao Qian
University: The Hong Kong Polytechnic University
Layman Summary
Mass spectrometry-based “-omics” studies such as proteomics, metabolomics and lipidomics, refer to systematic analyses of a large family of proteins, metabolites and lipids, respectively. Because of the rich information as well as robust reproducibility that omics approaches can provide, they have been widely used in in multiple disciplines of biology, chemistry, medicine and environmental science.
As research advances rapidly, we are analysing complex samples from bio-fluids, tissues, organs or even whole organisms frequently. However, such biological or patient-derived medical samples often have exceeding complexity, low amount and a large dynamic range, and thus pose great analytical challenges to mass spectrometry-based omics studies. To tackle these problems and meet the local need of omics studies, we propose purchasing and installing an ultra-speed mass spectrometer. The equipment takes advantage of a series of revolutionary technologies including ion mobility separation and provides unprecedented scan speed, detection sensitivity and quantification accuracy. The establishment of this ultra-high speed Mass spectrometer will stimulate collaborations, enhance the research competitiveness and train young scientists in Hong Kong.
Project Reference No. : C6001-19EF
Project Title : High-resolution adaptive optics microscope system for live and deep imaging of biological tissues
Project Coordinator : Prof QU, Jianan
University : The Hong Kong University of Science and Technology
Layman Summary
The human brain is the most complex living structure and in many ways it is considered as the final frontier of science. Disorders of the brain result in more hospitalization than any other disease group. State-of-the-art optical microscopy, particularly two-photon excited fluorescence (TPEF) microscopy with a transgenic mouse model of human brain disease can reveal the dynamic responses of cells to damage in a living mouse brain, providing key information for understanding the diseases and moving forward toward better prevention, diagnosis, and treatment. However, the imaging capability of TPEF microscopy is limited by distortion of the excitation laser’s wavefront caused by the optical inhomogeneity in imaging window interface(s) and in brain tissue. Here, we propose to build a TPEF microscope (TPEFM) with adaptive optics (AO) that will allow high-resolution imaging of the cortex and underlying deep structures such as the hippocampus. AO techniques can correct wavefront aberration from the window and tissues. The proposed AO-TPEFM platform will provide a unique tool not only for research into brain functioning and its disorders, but also for in vivo imaging of injuries and regeneration of the spinal cord, an extension of the brain. In a preliminary study, we have integrated an AO system with a TPEF microscope to demonstrate the capabilities of the proposed AO-TPEFM and shown that after AO correction the system can achieve near-diffraction-limited imaging in the brains and spinal cords of live mice. We have also developed and implemented algorithms and software for the AO system. We are now fully prepared to build a high-performance and user-friendly AO-TPEFM platform for general use by non-optical expert, particularly the biologist. In Hong Kong we have a strong team of internationally-regarded neuroscientists researching the functioning and disorders of the central nervous system, consisting of brain and spinal cord. So we now request equipment funding to set up an AO-TPEFM system with the unique imaging capabilities they badly need. That will involve acquiring an adaptive optics system, a femtosecond laser, a configurable TPEF microscope platform and high-performance objective lenses for multiphoton microscopy. In a preliminary study we have already demonstrated that the platform can potentially make significant impact on research in neuroscience and other fields of biology. We emphasize that although this proposal was initiated by the PI and a group of neuroscientists, the AO-TPEFM platform will be open for use by the whole research community of Hong Kong biologists.
Project Reference No. : C6021-19EF
Project Title : X-GPU: An Extreme GPU Cluster for Interdisciplinary Research on Molecular Dynamics Simulations and Genomics Studies
Project Coordinator : Prof HUANG, Xuhui
University : The Hong Kong University of Science and Technology
Layman Summary
Nowadays, many important scientific studies rely heavily on large-scale computations. Graphics processing units (GPUs) with hundreds of arithmetic units can process data in a highly parallel manner, and thus provide significant acceleration over central processing units (CPUs) for massive scientific computing. The rapid development of modern GPU hardware and programming platforms has enabled many recent scientific breakthroughs. Consequently, high-performance GPU clusters have emerged to a major frontier of scientific computing. Regrettably, current GPU-accelerated scientific computing studies in Hong Kong are all performed on small GPU clusters containing only tens of GPUs. This has severely limited the scale and caliber of these computation-intensive scientific projects such as modeling conformational dynamics of biomolecules, simulating phase transitions of condense matters, and analyzing genomic datasets.
We will establish an Extreme Graphics Processing Unit (X-GPU) cluster consisting of ~400 state-of-the-art GPUs. Once established, this X-GPU cluster would enable large-scale collaborative computing projects currently not possible in Hong Kong. Our X-GPU cluster will specialize in single-precision calculations, and will be applied to three specific scientific topics: molecular dynamics (MD) simulations of functional conformational changes of biomolecules, MD simulations of multiscale phase transitions, and integrative genomic data analysis. Although these projects are specialized, we expect that they will have a broad impact on chemistry, physics and biology: e.g. the development of next-generation antibiotics, the fundamental understanding of phase transitions, and the elucidation of the biological basis of cancer progression.
GPUs are more efficient than CPUs mainly because of their parallel processor architecture. However, this feature renders GPU clusters more difficult to program, especially for application scientists. Therefore, the key to success in GPU computing lies in the tight collaborations between computer scientists and application scientists. Our team consists of computer scientists and mathematicians with extensive experience in developing efficient GPU algorithms and open-source GPU software. They will work closely with our team’s application scientists (consisting of chemists, physicists, and biologists) to optimize and develop efficient algorithms on X-GPU and maximize their performance in specific scientific applications. We anticipate that the establishment of the X-GPU cluster will propel Hong Kong to the world’s forefront in GPU-based large-scale scientific computing.
Project Reference No. : C7045-19E
Project Title : Atomic-resolution Environmental Transmission Electron Microscope for Characterisation of Advanced Materials and Devices
Project Coordinator : Professor M. Huang
University : The University of Hong Kong
Layman Summary
A large number of scientists and engineers in Hong Kong are studying fabrication, characterisation and application of nano-materials and nano-devices. These studies require precise in-situ understanding of materials’ response to various chemical environments at atomic- and nano-scale by using atomic-resolution environmental transmission electron microscope (ETEM). The aim of this proposal is to establish the first atomic-resolution ETEM for share use among universities, research institutes and industries in Hong Kong. The proposed ETEM facility can serve as an excellent platform for interdisciplinary research among scientists and engineers in various disciplines in Hong Kong. With the help of the proposed ETEM, universities, research institutes and industries which carry out research in nano-materials ad nano-devices in Hong Kong can stay competitive and make contributions to the technology advancement in Hong Kong.
Group Research Proposals
Project Reference No. : C1005-19G
Project Title : Computational Design of Material Interfaces: application to the mechanical behaviour of aerospace materials
Project Coordinator : Professor SROLOVITZ David Joseph
University : The City University of Hong Kong
Layman Summary
Many of today’s most visible technologies depend on scientific and engineering developments in high-performance structural materials. Aerospace alloys are amongst the most advanced structural materials with immense economic and societal impact; advanced alloys are the crown jewel of modern industry. Their mechanical performance strongly influences aircraft reliability, performance and fuel efficiency. Like most engineering alloy, these are, in-fact, composites of different materials and phases. Remarkable properties are achievable by forming these phases on very fine scales; this implies that interfaces between these phases are of central importance. This project focuses on the science and engineering required to understand and predict the structure and properties of interfaces between dissimilar materials and their implications form acroscopic mechanical behaviour. We will develop computational materials science theory and tools that workover a wide range of scales to predict these properties; there by, providing a rational, scientific approach to develop and optimize high performance structural alloys.
Project Reference No. : C2009-19G
Project Title : Non-canonical NAD-capped RNAs in Arabidopsis: mechanisms of capping and decapping and molecular and physiological functions
Project Coordinator : Professor Xia Yij
University : Hong Kong Baptist University
Layman Summary
Gene expression is the process by which a gene (DNA) is converted into a functional product, such as a protein. Messenger RNAs (mRNAs) act as the intermediates in gene expression and carry the instructions for making proteins from genes. Cells modify mRNAs in different ways to mediate their functions. Eukaryotic mRNAs generally have a cap at their 5’ end that is termed the m7G cap. This cap mediates almost all steps of gene expression. Recently, it has been reported that some RNAs in both prokaryotes and eukaryotes have an NAD molecule as their cap. These findings indicate a novel mechanism in regulating gene expression through the NAD cap. However, the mechanisms of NAD capping and decapping and molecular and biological functions of NAD-capped RNAs (NAD-RNAs) remain to be defined.
We have developed a new method termed NAD tagSeq for identification, quantification, and characterization of NAD-RNAs. This method and other approaches will be used in this project to reveal how NAD-RNAs are produced and how the NAD cap controls gene expression in various plant biological processes using Arabidopsis as a model. The project will be carried out by a research team with complementary expertise. This study will make a significant contribution for understanding the functions of NAD-RNAs in regulating gene expression in all types of living organisms.
Project Reference No. : C4007-19G
Project Title : Widefield nanodiamond quantum sensing based on light-sheet microscopy
Project Coordinator : Professor LIU Renbao
University : The Chinese University of Hong Kong
Layman Summary
Diamond at size of hundreds of nanometers – nanodiamonds are ideal sensors for studying biological processes in single live cells, thanks to the high sensitivity of a kind of color centers – nitrogen-vacancy (NV) centres, which are composed of a nitrogen atom and a vacancy substituting a pair of carbon atoms in diamond. However, the detection of NV centres requires strong laser beams and the laser radiation would damage or even kill the cell under study – an effect called phototoxicity. This project would investigate a new method that use thin sheets of laser instead of focused beams to illustrate the cell in sensing live-cell functions using nanodiamonds. The light sheet can illuminate many pixels in a layer of cell and can be scanned freely along the vertical direction, allowing wide-field, 3D imaging and sensing of a live cell. This new method, solving the bottleneck issue of phototoxicity in applying nanodiamond sensors to live cells, will provide a new approach to exploring machineries in live cells, with high time and spatial resolution, capability of three-dimensional and even four-dimensional (space and time) sensing, and multi-modal sensitivity.
Project Reference No. : C4039-19G
Project Title : Exploiting epitranscriptome dysregulation in colorectal carcinogenesis and metastasis: mechanisms and novel therapeutic approaches
Project Coordinator : Professor YU Jun
University : The Chinese University of Hong Kong
Layman Summary
Colorectal cancer (CRC) is the number one cancer in Hong Kong. In contrast to an established role of genetic mutations, posttranscriptional mechanisms contributing to CRC remain largely unknown. Recent studies suggest that modification of RNA plays an important role in cancers. RNA N6-Methyladenosine (m6A) is the most abundant RNA modification cancer, however, whether and how m6A modifications may provoke a tumorigenic signal is unclear. Our preliminary data suggest that m6A deregulation has a major role in CRC. We identified a profound up-regulation of YTHDF1, a m6A reader that interprets m6A patterns in human cells, in CRC tumors compared to normal colon tissues. Subsequent investigations show that YTHDF1 has multiple roles in CRC, such as promotion of tumorigenic and metastatic phenotypes, induction of cancer stem cells and suppression of tumor-specific immunity. Our novel integrative genomic platforms have identified potential downstream targets of YTHDF1, including ARHGEF2, Notch signaling and maintenance of genomic stability. In this study, we aim to 1) determine the function of YTHDF1-m6A axis in CRC using cell lines, organoids and transgenic mice models with knockin/knockout of YTHDF1, 2) elucidate its molecular mechanism of action, 3) unravel molecular targets in YTHDF1-expressing; and 4) evaluate clinical significance of YTHDF1 in human CRC. Our project will provide novel insights into how m6A deregulation contributes to CRC tumorigenesis and metastasis. Translation of our work into the clinic will have implications for improving disease diagnosis and treatment.
Project Reference No. : C4055-19G
Project Title : Using Advanced Neuroimaging to Predict Language and Cognitive Outcomes in Pre-Term Infants
Project Coordinator : Professor WONG Patrick Chun-man
University : The Chinese University of Hong Kong
Layman Summary
Children born preterm (< 37 weeks of gestation) are at greater risk for language and cognitive problems. For moderate-late (32 < 37 weeks) preterm children, the risk for language problems is especially pronounced. Although children’s group rank-order language performance is quite consistent across development, behaviorally based predictive models have yet to meet the standard of precision for predicting an individual child’s future language and cognitive status. If untreated, language disorders could lead to poorer academic outcomes, reduced employment prospects and lower earnings. Because early intervention is effective, especially for those whose problems are more severe, prescribing early treatment based on accurate predictions could prevent poor outcomes, saving society and families heartache, time, and financial resources. Advanced neuroimaging acquisition and analytic tools have the potential to more accurately forecast language and cognitive problems than behavioral measures alone. By using data- and hypothesis-driven approaches, this project will use these tools to construct neural predictive models to forecast language and cognitive problems in individual moderate-late preterm infants. Our three-year goals are to test prevailing hypotheses on the neuropathological origins of these disorders for Chinese-learning children and to create algorithms and methods that will ultimately meet the regulatory requirements for a medical device. Neural measures will be obtained from preterm infants, and their language and cognitive performance will be measured up to 2 years after initial neural testing. Machine learning techniques with cross-validation procedures will be used to construct neural predictive models by linking neural and behavioral data from one testing center. The resulting models will subsequently be externally validated with children from other centers to determine their generalizability. In constructing these models, we will also test competing hypotheses concerning the neural basis of acquisition of Chinese, which differs from Indo-European languages across many important dimensions. Specifically, we will test whether neural abnormalities measured by MRI more specific to the left Peri-Sylvian region, as opposed to global white matter abnormalities, predict future language outcomes. We hope to develop the first generalizable and patentable predictive models for Chinese-learning preterm children, to assist parents and educators in planning personalized early interventions
Project Reference No. : C5008-19G
Project Title : Study of Inhibitors Targeting Bacterial RNA Polymerase Holoenzyme Formation as Novel Antimicrobial Agents
Project Coordinator : Dr Ma Cong
University : The Hong Kong Polytechnic University
Layman Summary
Multi-drug resistant bacteria, or superbug causes increasing health burden worldwide. As a result, antibiotics with novel modes-of-action are urgently needed. RNA is made from DNA by the enzyme RNA polymerase (RNAP) in a process called transcription. In bacteria, a holoenzyme formed by RNAP and sigma factor (s) is required to specifically initiate transcription. RNAP holoenzyme formation is crucial for viability, conserved in bacteria but not in human. Therefore, it serves as an attractive target for developing new, safe and effective antibiotics. We first reported the discovery of small molecule inhibitors (C3) against bacterial RNAP holoenzyme formation by rational design and in silico screening. Some of the C3 chemical derivatives have antimicrobial activity against clinically significant pathogens at a level comparable to the marketed antibiotics, with low cytotoxicity against the human cell lines tested. We hypothesize that the inhibitors targeting bacterial RNA Polymerase holoenzyme formation are suitable for antimicrobial discovery. This proposal aims to evaluate the newly designed and synthesized C3 library to provide potential antibiotic drug candidates for further development. The whole package of this proposal will set up a comprehensive platform leading the research field of antibiotic discovery targeting bacterial transcription. Results from this proposal will provide the basis for the development of new classes of antimicrobial drugs with a novel mode-of-action, which will impact society by providing exclusive therapeutic potentials against bacterial infectious diseases. This proposal serves as the step stone for establishing a focused scheme to contribute to the world-class research excellence with multidisciplinary collaboration in antimicrobial drug discovery.
Project Reference No. : C5011-19G
Project Title : Multi-scale spatiotemporal single-cell in-situ analysis: Mechanism and biomedical applications
Project Coordinator : Professor Yang Mo
University : The Hong Kong Polytechnic University
Layman Summary
In biology and disease research, determining cell-to-cell difference of origin, state and function, down to single-cell accuracy is always an important and challenging task. However, the development of current technologies for single-cell analysis is fundamentally limited by two challenges. First, they lack simultaneous multi-scale mapping biomolecules in their native spatial and temporal context from single-molecule level to whole-cell level within individual living cells. In fact, most of the current single-cell analysis techniques can only measure an ensemble average over a large number of molecules at the whole-cell level for a certain time point such as single-cell sequencing and flow cytometry. Second, current single-cell measurements are limited to the study of a few genes at a time due to the requirement of spectral non-overlapping for fluorophores. Therefore, the development of multi-scale spatiotemporal single-cell in-situ analysis approach from single-molecular level, organelle level to whole-cell level is of great significance.
With our multidisciplinary team of researchers, we aim to take an integrative approach to address the main challenges for single-cell analysis. This project focuses on development of a hydrogel droplet based single-cell in-situ analysis platform based on super-resolution barcoding of various types of multicolor fluorescence resonance energy transfer (FRET) probes for multi-scale spatiotemporal single-cell analysis. Three types of FRET techniques including multicolor sm-FRET for gene detection at the single-molecule level, g-FRET for organelle activity detection at the subcellular level and UCNP-FRET for quantitative ensemble detection at the whole-cell level will be used for multi-scale screening. The spectral barcoding of multi-color FRET pairs based on super-resolution imaging analysis will provide nanoscopic barcodes with multi photo-transfer channels for analysis of a large number of biomolecule types. Hydrogel droplet microfluidics will generate single-cell laden microgels for high-throughput analysis in a natural 3D microenvironment. The established system will be applied for a deep study of cancer stem cell (CSC) plasticity and heterogeneity under various 3D mechanical microenvironment as well as the related drug resistance analysis. Success will help empower the new paradigm of single-cell analysis, in turn enabling new and fundamental questions in tumor heterogeneity and precision therapy to be addressed.
Project Reference No. : C6018-19GF
Project Title : Molecular regulation of quiescence and early activation in muscle stem cells
Project Coordinator : Prof WU, Zhenguo
University : The Hong Kong University of Science and Technology
Layman Summary
In vertebrates, adult muscle satellite cells (i.e., muscle stem cells, or MuSC) are absolutely indispensable for injury-induced muscle regeneration. In uninjured adult muscles, most MuSC reside in a quiescent state (a unique cellular “hibernating” state with minimum cellular activities and energy requirement). Upon muscle injury, these quiescent MuSC (QSC) are activated, re-enter the cell cycle to proliferate, and then differentiate and fuse to repair the damaged muscles. Interestingly, it takes much longer time (~36-48 h vs 8-10 h for cycling cells to go through subsequent cell cycles) for QSC to enter the first cell cycle, which is absolutely crucial and tightly regulated. Dysregulation during this period prevent QSC from reentering the cell cycle and result in severe muscle regeneration defects. It remains unclear how the transitions from QSC to cycling myoblasts are regulated. Here, using different mouse models we generated that display defects in early activation of adult MuSC, we propose to perform comprehensive and systematic molecular, cellular, and mouse-based studies in order to understand how adult QSCs are regulated to become cycling myoblasts upon muscle injury. Through such systematic and in-depth mechanistic studies, we hope that we will gain better understanding of the molecular, epigenetic, and signaling mechanisms that regulate quiescence and early activation of adult MuSC. The results from our studies will be beneficial to future development of MuSC-based regenerative medicine for the treatment of various muscle diseases including muscle atrophy (e.g., sarcopenia) in aged people.
Project Reference No. : C6023-19GF
Project Title : Developing non-fullerene organic solar cells with small photovoltage loss
Project Coordinator : Prof YAN, He
University : The Hong Kong University of Science and Technology
Layman Summary
Organic solar cells (OSC) are promising alternatives to the traditional silicon solar panels because they are flexible, semi-transparent, printable and environmentally-friendly. These properties make OSC suitable for new solar cell applications, such as building-integrated photovoltaics (BIPV), which cannot be realized with the existing silicon technology.
Historically, OSC are less efficient than commercial silicon panels. This is largely due to their large voltage loss. Recently, the OSC field has seen a rapid development of non-fullerene acceptor materials. These non-fullerene materials can achieve much smaller voltage losses, therefore enabling much improved efficiencies. Currently, the best-performing OSC materials can achieve up to 17% efficiency, which is comparable to the 20% benchmark set by commercial silicon panels.
Despite this achievement, the underlying photophysical and chemical mechanisms that enable such high efficiency have remained unclear to the research community. This hinders rational material and device development as required for technology transfer and commercialization. Addressing this problem based on fundamental optoelectronic and structural-chemical studies is the key objective of this project. This project will not only help unravel the science behind OSC, but it will also have significant technological and societal impacts by promoting the deployment of flexible solar panels in Hong Kong, where the government has recently launched a highly attractive feed-in-tariff scheme to accelerate solar cell installation.
Project Reference No. : C6025-19GF
Project Title : Study of topological and unconventional superconductors
Project Coordinator : Prof LAW, Kam Tuen
University : The Hong Kong University of Science and Technology
Layman Summary
Superconductors can conduct current without resistance. In the beginning of the last century, many superconductors such as mercury, aluminum and niobium were discovered. However, the microscopic mechanism of superconductivity was not known until fifty years later. It was explained by Bardeen, Cooper and Schrieffer (BCS) that superconducting states are formed when electrons with opposite spins are glued together to form pairs called Cooper pairs.
In the late seventies and eighties of last century, new types of superconductors such as high-temperature superconductors and so-called noncentrosymmetric superconductors were found. These superconductors have different Cooper pairs and thus different physical properties than the ones postulated by the original BCS theory and they are called unconventional superconductors. For example, high-temperature superconductors can still be superconducting at much higher temperatures than conventional superconductors.
About twenty years ago, it was realized that a kind of unconventional superconductors called p+ip-wave superconductors are topological superconductors which host Majorana modes. Importantly, the Majorana modes can be used for quantum computations which are immune to the perturbations from the environment.
Due to the novel properties of unconventional and topological superconductors, the study of these superconductors has become an important area of research. Importantly, there have been exciting breakthroughs in the study of unconventional and topological superconductors in recent years.
First, new ways to realize topological superconductors have been proposed by others and by our team. In particular, our team has come up with theoretical proposals which can strongly enlarge the experimental regimes of realizing topological superconductivity. Our experimental group has the ability to grow high quality topological materials and fabricate nanostructures out of these topological materials. Therefore, our team, which consists of a theorist and four experimentalists, is in an excellent position to make important contributions to the understanding of topological superconductors.
Second, atomically thin transition metal dichalcogenides (TMDs) were found to be superconducting and exhibit a wide range of interesting superconducting properties. We have studied TMDs extensively in the past few years and showed that many TMDs are promising materials for realizing topological and unconventional superconductivity. At the same time, our experimental team has the ability to grow some of the best TMD materials with record high mobility and has the ability to do measurements at extremely low temperatures and high magnetic fields.
With the wealth of expertise and experience in our team, we are ready to explore the novel topological and unconventional superconductivity in topological and TMD materials.
Project Reference No. : C6026-19GF
Project Title : Novel Antibiotics from Genome Mining and Diversity-oriented Synthesis
Project Coordinator : Prof TONG, Rongbiao
University : The Hong Kong University of Science and Technology
Layman Summary
The widespread use and increasing consumption of antibiotics have driven bacteria to develop multi-drug resistance, endangering many medical treatments and surgical procedures that rely on antibiotic control of bacterial infections. The increasing prevalence of alarming antibiotic resistance requires the development of novel antibiotics with new molecular scaffolds. Unlike conventional bioassay-based fermentation, we propose to exploit both global genome mining and diversity-oriented synthesis to discover new antibiotics in this collaborative research project.
Genome Mining: In the genomics era with a large volume of genetic information deposited in publicly accessible databases, we will employ a global genome mining approach to identify biosynthetic gene clusters (BGCs) encoding antibacterial natural products. Our current focus will be on the discovery of new decalin-fused macrolide/macrocycle (DFM) PKS antibiotics by mining GenBank of microbial genomes with antiSMASH because many decalin-fused macrocyles (DFMs) exhibit potent antibacterial activity with a different mode of action from known macrolide (erythromycins) antibiotics. In addition, we will explore genome mining as a way to discover new antibacterial NRP-PK hybrids using a similar bioinformatics pipeline.
Metabolomic Analysis and Bioassay: Once we have selected bacterial strains by the genome mining, we will buy the appropriate sources for fermentation. The extracts from fermentation will be fractionated and then assayed for possible antibacterial activity using the so-called ESKAPE bacteria. The fraction of interest will be subjected to metabolomics profiling using UPLC-MS/MS and the results will be submitted to the open-access server Global Natural Products Social Molecular Networking for analysis to identify new antibiotics, e.g., decalin-fused macrocycles.
Chemical syntheses and modifications: Before new antibiotics are identified by genome mining and metabolomics, efforts will be directed to the development of new and efficient synthetic strategies for the total synthesis of anthracimycin and related decalin-fused macrolides. Once new antibiotics have been identified, chemical synthesis of the identified antibacterial natural products will be initiated to secure a supply of natural products for comprehensive bioassays, and chemical modifications will be followed to provide a library of analogues to study the structure-bioactivity relationship (SAR).
As an alternative to the chemical synthesis, we will study the biosynthesis of the newly-identified antibiotics and clone and express the identified BGCs in a heterologous host to enhance the production of new antibiotics and to facilitate further bioengineering of the secondary metabolites.
Finally, we will investigate the mode of action of the newly-identified antibiotic leads from SAR and evaluate their resistance risk and toxicity.
Project Reference No. : C6027-19GF
Project Title : The Role of IL-33 in Synaptic Dysfunctions and Pathogenesis of Alzheimer's Disease
Project Coordinator : Prof Nancy Y. IP
University : The Hong Kong University of Science and Technology
Layman Summary
Alzheimer’s disease (AD), the most common form of dementia, afflicts more than 40 million people worldwide and is projected to rise significantly to ~130 million by 2050 as aging populations rapidly increase worldwide. Since AD is presently incurable and available drugs only offer symptomatic relief, there is a critical need for effective disease-modifying treatments. However, limited understanding of the complex disease pathophysiology continues to hinder drug development efforts. While it is well established that accumulation of toxic beta-amyloid (Aβ) peptides in the brain and formation of neurofibrillary tangles in neurons are key features of AD, recent studies also point to immune responses in the brain as critical contributors to AD pathogenesis and progression.
In the previous CRF project, the team sought to determine the roles of the immune protein interleukin-33 (IL-33) in AD pathology, building upon their earlier discovery that IL-33 administration in the AD mouse model reverses synaptic plasticity impairment and reduces levels of toxic Aβ. The results validated the beneficial actions of IL-33 in AD and confirmed its potential as a therapeutic intervention in AD and mild cognitive impairment (an early stage of dementia). Moreover, the investigations enhanced understanding of the relationship between the disturbed immune system and the pathogenesis of AD.
The proposed project continues to build upon the previous findings to establish a comprehensive understanding of IL-33’s effects in AD. Previously, IL-33 treatment was found to alleviate AD pathogenesis by regulating the functions of microglia, the major type of immune cells and first line of defense in the central nervous system. Specifically, IL-33 was found to regulate phagocytic activity of microglia and its inflammatory responses. Thus, in this project, detailed investigations will be conducted to investigate the molecular mechanisms underlying the functional state transition of microglia in IL-33-stimulated alleviation of AD pathology. Furthermore, detailed examination of the beneficial effects of IL-33 on hippocampal synaptic plasticity and memory functions will be conducted to elucidate the cellular mechanisms underlying the restoration of synaptic and memory deficits in AD. Moreover, given that there is a strong interrelationship between immune responses and tau pathology in AD, it is critical to examine whether IL-33 exerts roles to ameliorate tau pathology during the progression of the disease. Collectively, these studies will elevate understanding of the IL-33/ST2 pathway in AD, further validate the potential of IL-33 as an AD therapy, as well as identify new approaches for effectively monitoring and treating AD.
Project Reference No. : C7009-19G
Project Title : International Big Data Network for Attention Deficit and / Hyperactivity Disorder: Development and Application of Data Platform
Project Coordinator : Professor I.C.K. Wong
University : The University of Hong Kong
Layman Summary
Attention-Deficit/Hyperactivity Disorder (ADHD) is a neurodevelopmental disorder linked with a diverse range of adverse outcomes, such as substance abuse/addictive behaviour, increased suicidal risk, difficulties with social relationships, and poor academic/occupational performance. A recognised major global public health issue, ADHD affects 7.2% of children worldwide and 6.4% in Hong Kong, and ADHD-related adverse outcomes often persist into adulthood, placing considerable burden on health and social services.
This research project explores the utility of big data and the formation of a multinational research platform. Hong Kong has a routinely updated electronic health record database that contains de-identified (no identifiable personal details) clinical information from all publicly funded hospitals and clinics. There are currently a number of established child cohorts in Hong Kong developed by the research teams for various proposes. This project will conduct a feasibility study to develop a record linkage model to link ad hoc research data and routine data. The team will also conduct pilot studies to describe the characteristics of successful linkage patients and application of data to assess the impact of ADHD medication on risk of child maltreatment/abuses. Furthermore, we will conduct a proof-of-concept study to set up an international big data platform from multiple data sources worldwide.
Record linkage from multiple datasets is essential to investigate the long-term impact of ADHD and to inform policy makers on the effective management and support of patients throughout their life trajectory. The local and international research platforms will support future ADHD research on other long-term and rare outcomes, and more importantly, improve the education, social support, and medical care of patients with ADHD and their families globally.
Project Reference No. : C7013-19G
Project Title : What lies beneath: Human and environmental health risk factors in our ocean - an experimental application of MarineGEO-Hong Kong
Project Coordinator : Dr. D.M. Baker
University : The University of Hong Kong
Layman Summary
Biodiversity describes the entire variety of species on Earth. In the oceans, we are fascinated by charismatic fauna such as large fish and marine mammals. Yet, by comparison it is the tiny organisms in the sea that are the greatest in number and weight, which gives these tiny animals a disproportionate impact on how ocean ecosystems function. For instance, tiny worms and crabs inhabiting the seafloor may be too numerous to count. Like an urban sanitation crew, these animals contribute to nutrient recycling, waste removal, and in-turn are a critical source of nutrition that underpins important fisheries. This project seeks to expand our knowledge of marine biodiversity in our local ocean, and to help understand how human stressors like sewage, aquaculture, and sedimentation shape the diversity therein. By deploying passive samplers, small plastic “hotels” for marine life called ARMS, we can conduct censuses of marine life at the micro-scale. Moreover, our project will relocate these samplers (like a portable marine community) in an experimental design that will let us determine how those communities resist change, and recover from changes due to human activities. By doing so we can inform management efforts to restore our local marine environment. Moreover, our project will screen samples for pathogens and anti-microbial resistance, and ask whether promoting marine biodiversity can limit our exposures to these human health risks.
Project Reference No. : C7015-19G
Project Title : Measurement of the Neutrino Mass through the Effects of Relic Neutrinos on Cosmological Structure
Project Coordinator : Dr. J.J.L. Lim
University : The University of Hong Kong
Layman Summary
By combining expertise in astronomical measurements at HKU, cosmological simulations at CUHK, and theoretical cosmology at HKUST, we have made a preliminary determination of the absolute neutrino mass scale: ∑mν =(0.11±0.03) eV. This value is consistent with the minimum mass of 0.1 eV permitted by the inverted neutrino mass hierarchy, but not sufficiently precise to discriminate between this and the even lower minimum mass of 0.06 eV permitted by the normal hierarchy. Here, we seek to confirm our preliminary measurement by gathering more comprehensive astronomical data and conducting more exacting cosmological simulations, thus improving upon our measurement precision such as to potentially discriminate between the two neutrino mass hierarchies. A precise mass measurement will aid complementary laboratory experiments to determine the ordering of the neutrino mass hierarchy, and together guide physics beyond the Standard Model.
Project Reference No. : C7028-19G
Project Title : Integrative chemical biology approaches to decipher histone marks on H3K79
Project Coordinator : Dr. X.D. Li
University : The University of Hong Kong
Layman Summary
Histone posttranslational modifications (PTMs) underlie a primary cellular mechanism of epigenetic regulation of gene functions. Histone H3 lysine 79 (H3K79) is one of the residues that are frequently decorated by PTMs. Among the best known H3K79 modifications is methylation, which is ‘written’ by methyltransferase DOT1L. Little is known about how H3K79 methylation is translated to downstream processes as the specific protein effectors (‘readers’) of this mark have not yet been identified. Besides methylation, other PTMs including succinylation have also been identified at H3K79. While H3K79 succinylation was recently found to be link to brain tumorigenesis, much less is known about its regulatory mechanisms and cellular function. The completion of this project will offer new strategies to study the histone PTM-mediated interactions in a nucleosomal context. It will also provide insights into the understanding of how histone H3K79 modifications orchestrate the normal cell physiological and pathogenic events.
Project Reference No. : C7044-19G
Project Title : Functional and systems analyses of regulatory networks controlling cell fate and lineage development of intervertebral disc cells
Project Coordinator : Professor K.S.E. Cheah
University : The University of Hong Kong
Layman Summary
The intervertebral discs in the spine play essential roles in providing flexibility and buffering against compression force. In intervertebral disc disease (IDD), the functional capacity of the central core of the disc, the nucleus pulposus (NP), declines with age, which, together with the associated low back pain, are the leading cause of disability, with major impact on the economy and the quality of life of millions of people, globally. The underlying disease-causing processes are not well understood.
In humans, at birth the healthy NP is full of morphologically distinct cells resembling those in the fetus. During aging the cellular content of the NP changes, numbers decrease and their morphology changes. Signs of degeneration correlate with the appearance of other cell morphologies including fibroblast-like cells. The molecular character, functional roles and lineage relationships between these morphologically distinct cells are poorly understood.
Throughout life, NP cells are constantly subjected to multiple stresses such as lack of oxygen, nutritional deficit, mechanical load that lead to cellular stress responses, mediated by molecular pathways. The excess mechanical loading and changes of the extracellular matrix (ECM) surrounding the cells, lead to the stiffening of the ECM which can trigger mechano-sensitive activation of regulatory factors. The underlying molecular mechanisms are unclear. While restoring IVD function would be preferred over surgical repair, the development of restorative therapy needs comprehensive understanding of the disease-causing mechanisms and the functional attributes of human NP cells. We delineated, by analyzing single NP cells, the molecular signatures of human NP populations at different stages of life to provide insights into IDD. We found activation of multiple pathways and genes which implicate the stress responses, and TGFβ/BMP pathways. Specifically we identified three specific transcription factors that regulate expression of fetal-like NP genes and are candidate factors critical for maintaining the fetal and healthy character of NP cells.
In this project we aim to elucidate the molecular pathways and gene regulatory networks controlling NP cell identity and function, and their ability to adapt and respond to the extrinsic challenges. We hypothesize, in development and early life, activity of three putative candidate transcription factors contributes to maintaining healthy NP cells. With ageing, and prolonged oxygen and nutritional deprivation and exposure to mechanical load, the activity of mechano-sensitive transcription factors and stress response pathways promote gene regulatory changes, leading to transformation of the healthy NP cells into fibroblastic like cells that synthesize instead, a stiffened ECM. The combination of all of these changes lead to impaired function and IDD. To address the hypothesis, we aim to determine the inter-connecting roles of the putative critical transcription factors, stress response and other mechano-sensitive transcription factors in determining NP cell identities and fate. Towards that end, we will develop human pluripotent stem cell reagents to follow the differentiation of human NP cells and their lineage derivatives in vitro. We will use genetically modified NP cells, functionalized matrices, bioreactor and mouse models and advanced genomic technologies, to study the underlying molecular mechanisms that control NP cell differentiation and cell fate. Successful outcomes of the project are: fundamental knowledge about the molecular and cellular mechanisms of human NP development, and adaptation of the cells to stresses, applicable to IDD; suitable human cell sources for future cell-based therapies and screening drugs for IDD.
Project Reference No. : C7069-19G
Project Title : Psychological resilience and mental wellness: Effects of internal neurobiological affective and external social support systems
Project Coordinator : Professor T.M.C. Lee
University : The University of Hong Kong
Layman Summary
Globally, stress-related illnesses have become increasingly prevalent. For example, depression and anxiety are now the leading causes of disability worldwide. In Hong Kong, the prevalence of youth suicide particularly that of full-time students is alarming. The lack of any sign that these stress-related problems will decrease is worrisome and reflects the urgency for research to understand factors protecting people against the deleterious effects of stress. One critical factor is psychological resilience (resilience), which represents the ability to recover from stress and adversities. Resilience has been well-established as a multidimensional construct subject to dynamic regulation by complex interactions among neural, biological, social, and behavioral systems. Therefore, resilience can only be thoroughly understood through comprehensive examination of the relationships between the internal factors (neurobiological and affective) and external socioecological systems underpinning resilience. Furthermore, computational-modeling methodology is required and will be employed to integrate various multimodal data to provide reliable evidence for valid analyses that elucidate the relationship between the examined neurobiological/psychosocial mechanisms and resilience. Our project will generate significant insights to guide future resilience research. Practically, our work will be critical for the early identification of risk factors of stress-related disorders for timely intervention. Knowing how parameters of the studied and aforementioned internal and external factors correlate with resilience and thereby affect mental health will facilitate the development of large-scale educational strategies with considerable value for promoting mental wellness.