Theme-based Research Scheme - Fourth Round Layman Summaries of Projects Funded

Theme 1: Promoting Good Health
Project Title: Viral, Host and Environmental Determinants of Influenza Virus Transmission and Pathogenesis
Project Coordinator: Professor PEIRIS Joseph Sriyal Malik (HKU)

Influenza is a major threat to global public health. Pandemic influenza arises from animals at unpredictable intervals and can spread worldwide within weeks. Seasonal influenza is a predictable yearly occurrence that is associated with significant morbidity and mortality. Being a travel-hub situated in a region of infectious disease emergence, Hong Kong is under particular threat by this emerging and re-emerging infectious disease; examples being avian influenza H5N1 since 1997, pandemic H1N1 in 2009, and avian influenza H7N9 in 2013.

In the course of a previous Areas of Excellence program from the UGC, we established a multi-disciplinary influenza research program which has contributed to public health responses locally and globally. We now propose to address two major outstanding research questions in influenza. These are

i) the biological determinants of influenza virus transmission from animals-to-humans and from human-to-humans; and
ii) the immunological mechanisms protecting from or contributing to severe influenza disease.

We aim to define the viral, host and environmental factors that allow animal viruses to adapt to humans. This will help risk-assessment of animal viruses for pandemic or zoonotic threat and enhance global pandemic preparedness and provide evidence-based interventions to contain emerging threats. We will investigate the factors that pre-dispose to transmission of seasonal influenza viruses in humans by studies of influenza transmission within families and within hospital settings. These studies will help provide understanding of the mechanisms of influenza transmission and will allow evidence based interventions that can reduce influenza virus transmission within the community and within hospitals (e.g. better designed hospital wards and isolation rooms).

The immune responses to influenza are not completely understood and they can be either protective or harmful. Our studies will define these protective or harmful immune responses. We recently discovered new immune mechanisms including the role of γδ1-T cells and a novel innate immune sensor TLR-10 that contributes to protection or disease in influenza, and these and other mechanisms will be systematically investigated.

Understanding the mechanisms of acute lung injury in influenza is important so that novel therapeutic approaches that target the host can be devised for treating patients with severe influenza disease.

This program is an inter-disciplinary collaborative project involving The University of Hong Kong, the Chinese University of Hong Kong and the Hong Kong University of Science and Technology. It will enhance global public health, provide high quality research, intellectual property, real-time data to inform local, national and global health policy, train the next generation of scientists and help maintain and enhance Hong Kong's world-leading status in influenza research.

Theme 1: Promoting Good Health
Project Title: Genetics and Functional Genomics of Neural Crest Stem Cells and Associated Disease: Hirschsprung Disease
Project Coordinator: Professor TAM Paul Kwong-hang (HKU)

Hirschsprung disease (HSCR), one of the most common causes of neonatal intestinal obstruction, imposes a significant health care and economic burden, especially in China, where the disease has one of the highest incidences in the world (1.4/5,000 live-births versus 1/5,000 live-births in Caucasians). It is more common in males than in females. The cause lies in problems in the developmental pathway whereby neural crest cells, a multipotent stem cell-like population, capable of differentiating into several lineages, generate all the neurons and associated glia of the vast enteric nervous system, which is essential for gut motility.

HSCR is a complex disorder, in which genetic and, probably, environmental factors contribute to the severity, resulting in what are called different phenotypes. The genetic risk factors and detailed underlying mechanisms remain unknown, including the reason for the male gender bias. As a first step to understanding the disease, we and others have identified several genes that are crucial for development of the enteric nervous system. These genes act in a network to control the differentiation of neural crest cells into various enteric neurons and glia. When they function incorrectly, HSCR results. However, these genes do not account for all of the observed cases or types of HSCR. We therefore predict that there are unidentified genomic variants that affect the gene regulatory network in the neural crest cells and cells of the enteric nervous system. The challenges are to identify these genetic factors, to define more accurately how they regulate formation of the enteric nervous system, how their malfunction gives rise to HSCR, and to integrate the knowledge gained to model and understand the disease, including the male bias. To do this, we will use the latest techniques to generate stem cells from specific patients, called induced pluripotent stem cells that carry the same genetic mutations as the original patients. Because we need to study what happens in vivo as well as in cultured cells, we will look at mouse models of the disease. We have developed transgenic mice carrying very specific mutations to dissect the roles of different genes in the regulatory pathways.

As an internationally recognized multidisciplinary team of clinicians and scientists with a successful history of collaboration, we will address the challenges by building on: a) our unique collection of fibroblasts and induced pluripotent stem cells from patients with HSCR, DNA samples from over 700 Chinese HSCR patients, and comprehensive clinical information and genomic data for some of these subjects; b) a rich collection of mouse models for the disorder; and c) our expertise in statistical genetics, genome biology, biochemistry, developmental genetics, and stem cell biology. We will identify novel genetic variants associated with HSCR. Using induced pluripotent stem cells carrying different mutations, we will determine the roles of different genes in the development of neural crest cells to neurons and glia in the gut. By integrating information from these human model systems and their animal counterparts, we will test hypotheses of disease mechanisms. From this research, we will gain new understanding of the biology of HSCR, which can be used for more accurate diagnosis and risk stratification of patients with Hirschsprung disease to improve prognosis and enhance clinical outcome after surgery. Our long-term goal is to instigate a paradigm shift in the clinical diagnosis of HSCR, permitting stratified patient care and laying the foundation for novel reconstructive treatment.

This will improve the quality of life of children with these congenital malformations and of the families
at risk of having an affected child or who care for one.

Theme 2: Developing a Sustainable Environment
Project Title: Sustainable Power Delivery Structures for High Renewables
Project Coordinator: Professor HILL David John (HKU)

This proposal addresses the sustainability of electrical power delivery systems. Many countries and electricity company groups are already committed to increase renewable electrical energy generation to 20% by 2020, and some have much higher figures. It is now clear that energy sustainability refers to the complete network (or grid) which delivers the power as much as the sources of energy. This package of energy supply and grid can make a major contribution to solving the urgent and potentially devastating problems of pollution and climate change.

Further, there will be no universal solution, so Hong Kong with ambitious goals for emissions reductions, islands, tall buildings and a strong interconnection to China, where massive developments in renewable power are occurring, will need its own investigations. This is particularly important at this time when future energy security options must be considered within the emissions targets. Much higher use of renewable power, including offshore wind-power (and demand management), is under serious consideration already. The proper operation of an electricity grid involves an intricate set of balancing processes for energy, power, ramping all while achieving the regulation of system variables, e.g. voltages, frequency, line powers, and keeping the system protected and secure following disturbances. This is achieved with layers of system control (and market) processes. These processes all need to be redesigned for high levels of renewable power due to the weather driven variability of the power supply. Some studies have been made by governments worldwide to answer the question: what percentage levels of renewable energy are achievable? The question should also include asking what are the corresponding network structures that can be cost effective and robust to all the changes over coming decades? It is possible that this is all limited by stability problems caused by the variable generation. Our research is aimed to determine the structure of the delivery systems, which can overcome any such limitations and be sustainable in the long-term, including the appropriate system wide information and control systems.

The basic requirement is instantaneous balance of power generation and load demand in - 4 - order to maintain a stable frequency. The traditional paradigm of generation following demand, where millions of diverse customer actions are balanced with the controlled output of a small number of major generation plants, cannot handle the distributed and variable nature of solar and wind energy sources. We will study a new paradigm, which is adaptive in the sense of demand following generation. The load devices contribute to overall balancing and welfare of the system in processes of demand response and load control. Thus future smart loads, using advanced power electronics, and the control and communication systems must themselves be adaptive to the dynamically changing power generation and circumstances.

The four research teams will be led by internationally renowned experts in the key areas: power systems, power electronics, computer networking and control technology. The investigators will add special skills for particular projects. By integrating these areas in a balanced way, the aim is to build a unique research capability which can support the future industry in the Pearl River Region and beyond. The team will build on several of its own highly innovative ideas that have shown promise for the proposed research, namely (i) electric springs, (ii) granular modelling and control and (iii) adaptive networking (integrated with communication, control and security). It will collaborate with other researchers towards establishing Hong Kong as a central contributor in the vital area of sustainable electricity supply with benefits for the broader China area.

Theme 3: Enhancing Hong Kong's Strategic Position as a Regional and International Business Centre
Project Title: Title: Delivering 21st Century Healthcare in Hong Kong -Building a Quality-and-Efficiency Driven System
Project Coordinator: Professor CHEN Frank Youhua (CityU)

Healthcare delivery worldwide has been fraught with high cost, low efficiency and poor quality of patient care service. Hong Kong is no exception, and the quality of service provided to patients has been far from exemplary. For instance, it is not uncommon that the waiting time for certain routine surgeries at public hospitals could be as long as 18 months. Further exacerbating the problem is the aging population: the number of people of age 65 and above is fast approaching 15% of the general population in Hong Kong, and this statistic is increasing by about one percentage point every year. The objective of this project is to help Hong Kong develop a quality-and-efficiency driven healthcare delivery system that is built upon data analytics and compatible to the Internet age. Our research plan calls for in-depth studies on problems in two topical areas: (1) hospital resource planning, (2) healthcare data analytics; it is to address an important issue -- "better care at affordable cost." Novel features of the project include: addressing healthcare delivery in Hong Kong in the context of business services innovation, the focus on quality-and-efficiency driven strategies and systems-oriented solutions, and the emphasis on networked resources and human-centric characteristics in healthcare delivery. We have assembled a team of specialists, local and international, with a multi-disciplinary nature. Members are established experts with an excellent track record of academic publications, practical applications and collaborative research.