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Theme-based Research Scheme 2018/19 (Eighth Round) Layman Summaries of Projects Funded

Theme 1: Promoting Good Health
Project Title: Potentiating Host Immunity for HIV-1 Functional Cure
Project Coordinator: Professor Zhiwei Chen (HKU)

Abstract
HIV-1 is the causative agent of AIDS. HIV-1 continues to spread, leading to 36.9 million people living with the virus and about 40 million deaths worldwide. In Hong Kong, despite active prevention and timely introduction of combination antiretroviral therapy (cART), the number of cumulative infections has increased from 776 in 1996 to 8,952 in 2017. Financially, the annual cART cost alone has increased to about HK$550 million in 2015-16. Since the life-long cART is unlikely sustainable and cannot cure HIV/AIDS, our overall objective is to develop a combination immunotherapy of potentiating host immunity to achieve a functional cure, a state of suppressed viremia below detection limit for a prolonged period in HIV-1 patients without receiving cART.

With previous supports from RGC General Research Fund/Collaborative Research Fund and Health and Medical Research Fund (HMRF), we have made several important findings, leading to our hypothesis that PD1 vaccine-based combination immunotherapy will provide a prolonged viremia control by potentiating host immunity. First, PD1-based vaccine elicits high frequencies of potent HIV- 1-specific cytotoxic CD8+ T lymphocytes (CTLs). In pilot experiments, 4/4 rhesus monkeys vaccinated with a rhesus PD1-based vaccine showed a prolonged viremia control after infection by a monkey AIDS virus, called simian-human immunodeficiency virus (SHIV162P3). Second, we have engineered a potent tandem bi-specific broadly neutralizing antibody, namely BiIA-SG, that blocks two essential steps of viral entry into target cells at the same time and controls HIV-1 infection in humanized mice. Furthermore, BiIA-SG prevents SHIV162P3 infection in 3/3 monkeys completely and suppresses viral replication in 6/6 animals in post-exposure experiments. Third, we defined a Δ42PD1-TLR4 immune regulatory pathway and identified a blocking antibody that reduces HIV-induced intestinal pathology. Fourth, we found that human myeloid-derived suppressor cells (MDSCs) are critical for suppressing CTLs and conferring immune-checkpoint blockade resistance. Based on these findings and our team’s expertise, we apply for this TRS to conduct a five-year comprehensive project to study PD1 vaccine-based combination immunotherapy in monkey models and human subjects.

Using modern virology and immunology methods, we focus on three specific research themes: (1) To determine correlates of PD1-based vaccine- and BiIA-SG-induced protection in SHIV162P3-infected rhesus macaques, (2) To determine immunogenicity and efficacy of GLP-grade human PD1-based vaccine and BiIA-SG in animal models in support of investigational new drug (IND) application, and (3) To investigate the possible functional cure of HIV-1 infection in patients. The results are expected to enrich our knowledge on mechanisms of immune protection which are critical for saving patients’ lives, reducing cART toxicity/resistance, as well as governmental and patients’ financial burden.


Theme 1: Promoting Good Health
Project Title: A Stem Cell Approach to Dissect the Molecular Basis of Neurodegenerative Diseases
Project Coordinator: Prof Nancy Ip (HKUST)

Abstract
The project aims to address the urgent need for new and innovative therapies that can treat age-related neurodegenerative disorders such as the highly prevalent and devastating Alzheimer’s disease (AD). AD primarily affects the elderly, and is characterized by memory loss and impaired movement, reasoning and judgment. The disease progressively worsens over time, resulting in massive disease burden to patients, their caregivers, and societies. There are currently no effective treatments to reverse or halt the progression of AD, whereas disease prevalence is rapidly increasing due to aging populations worldwide. Without effective clinical interventions, healthcare services around the world will eventually face dire consequences.

This project builds upon our previous TRS-funded research, which unravelled some of the complex mechanisms governing the regulatory pathways that underlie neurogenesis and differentiation of neural stem cells, and led to the discovery of a number of small molecules that stimulate endogenous neurogenesis. Here, we aim to dissect the pathological mechanism of AD by leveraging our previous findings. To identify disease pathways and novel therapeutic targets, we plan to draw on the power of human induced pluripotent stem cell (iPSC) and CRISPR-Cas9 genome-editing technologies. These state-of-the-art technologies will enable us to generate and utilize patient-derived iPSCs to conduct detailed investigations on the pathophysiology of AD. In our foundational TRS, we identified several potential drug leads with memory enhancing activity. Hence, we will also undertake preclinical development of these drug leads.

Successful completion of the project will bring us one step closer to developing novel therapies that can halt or reverse the devastating effects of AD, thus improving millions of lives worldwide. The project will also enhance Hong Kong’s growing reputation as a center for research excellence, while placing Hong Kong on the map for advanced neural regenerative medicine and stem cell research.


Theme 2: Developing a Sustainable Environment
Project Title: Sustainable Marine Infrastructure Enabled by the Innovative Use of Seawater Sea-Sand Concrete and Fibre-Reinforced Polymer Composites
Project Coordinator: Prof Teng Jin-Guang (PolyU)

Abstract
Coastal cities like Hong Kong rely heavily on their coastal and marine (referred to as “marine” hereafter for brevity) infrastructure (e.g., ports, bridges, artificial islands and offshore wind farms) for social-economic development. A major challenge for marine infrastructure is steel corrosion, which is the main cause for infrastructure deterioration. Typically, steel corrosion costs an economy around 3% of its GDP (3% of Hong Kong’s GDP in 2016 = US$9.6 billion). The American Society of Civil Engineers (ASCE) estimated in 2013 that US$3.6 trillion would be needed from 2013 to 2020 to maintain a state of good repair for the US infrastructure. Another major challenge for marine infrastructure is the shortage of fresh water and river sand (or crushed stone fines) for making concrete. Apart from the negative environmental effects of consuming great amounts of fresh water and river sand/crushed stone fines, their transportation is both expensive and environmentally detrimental; desalination of seawater and sea sand is also costly.

This project aims to address both challenges by developing a new type of concrete structures to achieve sustainable marine infrastructure: seawater sea-sand concrete (SSC) structures reinforced with fibre-reinforced polymer (FRP) composites (e.g., FRP bars and tubes) (referred to as FRP-SSC structures). As FRP composites have excellent corrosion resistance and are highly durable, they are gaining increasing acceptance as replacement of steel in conventional reinforced concrete structures in aggressive environments (e.g., bridge decks exposed to dicing salt). By capitalising on the durability of FRP composites, seawater and sea sand can be directly used in constructing marine infrastructure. FRP-SSC structures will revolutionise the construction of marine infrastructure.

For FRP-SSC structures to be widely used, extensive research is needed to gain an in-depth understanding and develop design and construction methods. Although FRP composites do not corrode, they do deteriorate, although only slowly, in aggressive environments. The key scientific challenge for the project is to understand and predict the life-cycle behaviour of these structures and to develop a life-cycle design methodology. While past research on material/structural performance deterioration has relied primarily on the direct empirical extrapolation of accelerated laboratory test results to real-time performance, this traditional approach has been increasingly questioned as being highly uncertain/unreliable. In the proposed project, a new approach based on multi-scale multi-physics modelling of material and structural deterioration will be established and verified with rigorous experimentation to predict the life-cycle performance of FRP-SSC structures.


Theme 3: Enhancing Hong Kong’s Strategic Position as a Regional and International Business Centre
Project Title: Contributing to the Development of Hong Kong into a Global Fintech Hub
Project Coordinator: Prof Kar-yan Tam (HKUST)

Abstract
Hong Kong aspires to become a global fintech hub and needs to keep abreast of technology, adapt its regulatory environment, and strengthen its fintech ecosystem. To maintain its competitive edge, Hong Kong must move beyond replicating fintech practices elsewhere and develop its own insights and strategy most suited to the trajectory of its economy. The project aims to build the intellectual foundation of a grand strategy on fintech for Hong Kong by developing a deep understanding of the interplay between technology and financial services. Specifically, the project has two goals: (1) To establish Hong Kong as an intellectual powerhouse of fintech; and (2) to assess Hong Kong’s ability to facilitate financial innovations and to develop policy recommendations to sustain fintech development in Hong Kong. The project will address fundamental issues related to the impact of fintech on individual investors, financial institutions, regulators, and the finance industry as a whole. These issues are intellectually challenging and practically relevant. They sit at the intersection between technology and financial services and underpin a wide spectrum of services including digital payment, financial product design and distribution, robo-advising, public disclosures, cybersecurity, risk management, and distributed ledger applications. A wide spectrum of topics will be addressed including blockchain, cybersecurity, personalized risk assessment, robo-advising, applications of AI/machine learning in multimodal analysis of financial disclosures, modeling systemic risk using advanced quantitative techniques, analyzing fintech services to address policy questions, and fintech manpower development. In view of the interdisciplinary nature of fintech, the project is led by experts in accounting, economics, finance, computer science, information systems, and statistics from HKUST, CUHK, CityU and HKU. The project will generate state-of-the-art research findings, from which a grand strategy of fintech development for Hong Kong will be developed with policy recommendations on the regulatory environment, innovation pipeline, cooperation between incumbents and startups, and the recruitment and nurturing of fintech talent.


Theme 4: Advancing Emerging Research and Innovations Important to Hong Kong
Project Title: Image-guided Automatic Robotic Surgery
Project Coordinator: Prof Yunhui Liu (CUHK)

Abstract
Robotics is widely considered to be one of the key technological drivers of economic growth and competitiveness. It therefore is important for Hong Kong to develop its own robotics technology. The challenge lies in where to position Hong Kong in this extremely broad interdisciplinary area. Since Hong Kong has the best healthcare system in the region, developing robotics technology for healthcare is an obvious strategy, which will build upon our existing strengths.

The objective of this project is to establish a world-class research center in surgical robotics in Hong Kong by forming an interdisciplinary team with the necessary expertise in engineering and medicine from local universities, and collaborating with internationally-respected institutions such as Intuitive Surgical Inc., Imperial College London, and Johns Hopkins University. Existing surgical robots work in a remote control mode in which a surgeon tele-controls the robots with full attention. It is widely considered that such remote-controlled robots will be replaced by next-generation ones that will assist surgeons with high-level intelligence, and automatically perform particular steps of surgical procedures. The development of such intelligent surgical robots presents several big scientific challenges including (1) how to efficiently and reliably sense surgical objects/fields; (2) how to automatically carry out pre-operative (pre-op) surgical planning and navigate the robots in the highly dynamic and individual-dependent environment; (3) how to control the actions of surgical robots safely and accurately; (4) how to equip surgical robots with high-level intelligence, e.g., the abilities of situation awareness and reasoning. By combining the expertise and experiences in the different areas, we aim to develop innovative solutions to those challenges, which include (1) novel systems and algorithms for real-time sensing of 3D geometry, force, and biomechanical properties of surgical objects; (2) data-driven surgical planning and navigation by using the huge image data of robotic surgery at the Prince of Wales Hospital (PWH) and Intuitive Surgical Inc.; (3) visually servoed controllers for robots interacting with soft tissues; and (4) robotic surgery intelligence based on deep learning. The technologies will be integrated into a prototype of image-guided surgical robots that is able to automatically assist surgeons and perform a single surgical step or several connected steps of surgical procedures. We will use the total laparoscopic hysterectomy (TLH) as the example to validate the system by ex-vivo experiments, and if approved, by clinical trials and pilot applications.