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NSFC/RGC Joint Research Scheme 2012/13 Supported Applications - Layman Summaries of Projects Funded in 2012/13 Exercise

Interfacial Engineering of Graphene Heterostructures and Its Device Applications

Hong Kong Principal Investigator: Prof. Jianbin Xu (The Chinese University of Hong Kong)
Mainland Principal Investigator: Prof. Xinran Wang (Nanjing University)

Graphene is of considerable scientific and technological interests. The award of a Nobel Prize in Physics to K. S. Novoselov and A. K. Geim in 2010 for their pioneering work on graphene clearly indicated its importance. A fundamental understanding of the extraordinary electronic, chemical, and optical properties of graphene in combination with its surroundings is vital in many applications, including transistors, high-frequency transceivers, biosensors, and hybrid multifunctional devices. This proposal is focused on the interface engineering of graphene heterostructures that can potentially be used as the active and passive components of large area, flexible, and low-cost electronic/optoelectronic devices. Understanding the interfacial properties of graphene heterostructures is essential to device design and will lead to high performance and efficiency. The proposal covers three related topics focusing on graphene heterostructures that will eventually find practical applications, namely (1) development of new strategies for fabrication of graphene heterostructures with controlled doping and designed structural characteristics, (2) investigation of electronic and optoelectronic properties of graphene heterostructures, and (3) exploration of novel device architectures for high performance electronic and optoelectronic devices.

The Key Technologies Study for Deformable Bionic Search Robot with Electric Fabric Skin

Hong Kong Principal Investigator: Prof Xiaoming Tao (The Hong Kong Polytechnic University)
Mainland Principal Investigator: Prof Zhong Su (Beijing Information Science & Technology University)

Frequent occurrence of natural disasters like earthquakes and landslides make search rescue of human lives very challenging tasks. The unpredicted environmental conditions and complexity involved demand urgently the research and development of bionic deformable search robot which have special sensing and adaptation capacity. This project is concerned with the key technologies of novel deformable bionic search robot with electric fabric skin that can sense environmental conditions real-time dynamic data of temperature, humidity, noxious gas and mechanical stress/strain, dielectric elastomer actuator capable of mimicking gaits of snakes or earthworms, plan routes, based on information obtained from the sensors and camera, by SLAM algorithm, and vary its size and structure to adapt different routes in narrow space. The deformable bionic search robot with the electric fabric skin to be created and investigated in the project can provide full autonomous route planning and behavior control as they have whole-space sensing capacity. Deformable bionic search robot has an exciting aspect as it may pave the way to perceive the conditions in pipeline, aircraft engine or disaster fields and search lives in unknown and complex space such as ruins.

The project will conduct a scientific investigation of the mechanisms, design and control algorithms, fabrication processes and characterization of such bionic search robot. Five complex and challenging issues will be addressed. The first issue is to study, design, fabricate and evaluate novel deformable mechanical structures that can adjust its shape such as height, width and length to adapt the search route. The second issue is to design, fabricate and evaluate the stretchable electric fabric skin which can satisfy the deformation of the robot without damaging the whole-space sensing capabilities of physical quantity such as temperature, humidity, noxious gas, etc. The third issue is to study, design, fabricate and evaluate the bionic dielectric elastomers actuator which can drive the bionic search robot in snake-like or worm-like motion and their driving device/ control algorithm in low voltage and fast response. The fourth issue is the SLAM algorithm to planning the search route autonomously. The final task is to integrate a novel prototype bionic search robot based on the knowledge and technology developed in former four parts.

Searching and Browsing Cyber-Physical Objects

Hong Kong Principal Investigator: Prof Jiannong Cao (The Hong Kong Polytechnic University)
Mainland Principal Investigator: Prof Minyi Guo (Shanghai Jiao Tong University)

Recent years have witnessed the rapid advance in technologies and increases deployment of embedded sensing devices, wireless networks, and mobile computing systems. Sensing tags, smart objects, various kinds of nodes with computing and communication capabilities are immersed into our living environments, creating an environment of smart objects that integrate the cyber and physical worlds. Soon in the near future, we will be offered the opportunities to access the information about objects in the physical world, in addition to finding information in the cyber space on Internet. However, to achieve this goal, we are facing new challenges and need to develop new methods and techniques. In this project, we propose the framework and methodologies for collecting, searching and browsing the desired information about objects in the integrated cyber and physical worlds (hereafter called cyber-physical objects). We develop the architecture, algorithms and mechanisms to acquire, organize and store the information about the cyber-physical objects, create and maintain the contextual links between the objects, and to navigate from one object to others through the links, in a way much similar to searching the cyber world on the Web nowadays.
The major issues to be investigated include (1) Model the cyber-physical objects and their contextual relationships. (2) Design a framework including system architecture and major functional components, with networking and computing mechanisms, algorithms, and middleware support, for finding, storing and searching the information about cyber-physical objects. (3) Develop techniques for the construction and maintenance of the contextual relationships between cyber-physical objects and design the user interface for browsing and navigating the objects following the contextual links. We will also develop programming abstractions and tools to help programmers develop high-impact domain specific applications.
We foresee increasing demand of the technology to be developed in this project in our everyday life, as evidenced by the recent research and development in the areas of Internet of Things, Wireless Sensor Networks, and Ubiquitous Computing. This project will make original and important contributions to and have impact on a broad range of research areas, including distributed computing, mobile and wireless networking, database systems, and information searching. The output of this work has many important applications, such as smart space, social networking, logistics, intelligent transportation, pervasive-care, and intelligent construction and building management. The contribution of this project is also highly relevant and has special significance to both the industrial community and the society.

Cross-layer Analysis and Optimization for the Lifetime Reliability of MPSoCs

Hong Kong Principal Investigator: Dr. Qiang Xu (The Chinese University of Hong Kong)
Mainland Principal Investigator: Dr. Huazhong Yang (Tsinghua University)

With the relentless CMOS technology scaling, the lifetime reliability of complicated multi-processor system-on-a-chip (MPSoC) has become a serious challenge for the semiconductor industry. Existing works in this domain either focus on circuit-level analysis and optimization without considering the impact of runtime workloads or investigate high-level solutions assuming all devices are equally vulnerable. Due to such oversimplified assumptions, these solutions have substantial limitations for MPSoC lifetime reliability analysis and optimization. By considering the inherent correlations between failure mechanisms at device-level and the impact of runtime workloads at high-level, in this project, we plan to develop a full-system simulation framework for the lifetime reliability of MPSoC designs, which are expected to be much more accurate than existing solutions. With the help of the simulator, we further explore different MPSoC design alternatives and develop optimization techniques to meet the system lifetime reliability requirement without incurring high hardware/performance overhead to the design. Finally, we plan to investigate online dynamic reliability management policy optimization techniques to achieve better tradeoff between system performance and lifetime reliability for individual MPSoC products, by analyzing the information collected from various sensors placed in the design.

Mechanistic Analysis of Palmitate Transferase DHHC11 that Regulates Multiple Developmental and Cellular Processes

Hong Kong Principal Investigator: Prof Liwen Jiang (The Chinese University of Hong Kong)
Mainland Principal Investigator: Prof Yan Zhang (Shandong Agricultural University)

Plants are critical for the survival of human society by providing food, energy and chemicals. In recent years, population explosion and environmental changes caused by human activities have posed a great challenge facing plant biologists to optimize plant development and improve plant resistance to abiotic stresses for sustainable agriculture.
Plant vacuoles are acidic organelles that are critical for a variety of functions including nutrient remobilization, maintenance of turgor pressure, sequestration of toxic compounds, ions and secondary metabolites, and accumulation of storage proteins. Vacuole function is performed mainly by vacuolar membrane proteins, i.e tonoplast proteins, including vacuolar H+-ATPase, vacuolar PPase, Ca2+-ATPases, Ca2+/H+ antiporters, K+ and Na+/H+ antiporters, tonoplast intrinsic proteins etc. Functional loss of these tonoplast proteins often resulted in severe developmental defects and compromised responses to abiotic stresses. Recent studies suggested that tonoplast proteins are delivered to vacuole by vesicle trafficking routes via trans-Golgi network (TGN) and prevacuolar compartments (PVC). However, molecular and cellular mechanisms underlying such dynamic vesicle trafficking are far from understood.

We recently identified a novel component critical for vacuolar trafficking. Arabidopsis DHHC11 encodes an evolutionarily conserved palmitate transferase, whose family members catalyze the addition of palmitate group to cysteine residues of substrate proteins thus facilitates tighter membrane anchoring or distribution at membrane microdomains. Functional loss of DHHC11 resulted in pleiotropic defects including reduced biomass production, sterility, and hypersensitivity to abiotic stresses, suggesting defective vacuole function. Our results show that DHHC11 localizes at PVC and tonoplast, likely regulates vacuolar trafficking of tonoplast-localized ion transporters.

We propose to study the molecular and cellular mechanisms underlying DHHC11-regulated development and abiotic stress responses. Specifically, we will 1) identify developmental processes regulated by DHHC11 by characterizing DHHC11 loss- and gain-of-function mutants; 2) studying their sensitivities to abiotic stresses and analyzing genetic pathways in which DHHC11 plays a role. Although plant genomes encode a large number of DHHC-type palmitate transferases, none of which have been reported for their intracellular distributions that are critical for their functionality. We plan to 3) dissect DHHC11 to find out the critical domains/residues conferring its intracellular distribution. Finally, we will 4) use mating based split ubiquitin yeast two hybrid screening to find out interacting proteins of DHHC11. Knowledge gained from functional analysis of DHHC11 will not only provide insights into vacuolar trafficking routes of tonoplast proteins, but also build a theoretical basis for optimizing plant development and enhancing plant resistance to abiotic stresses.

Molecular Mechanism of Notochord Formation Regulated by XBP1

Hong Kong Principal Investigator: Dr. Hui Zhao(The Chinese University of Hong Kong)
Mainland Principal Investigator: Prof Ying Cao (Nanjing University)

The goal of our proposed research is to investigate the molecular mechanism of XBP1 in notochord formation. The notochord is found in all phylum chordates including humans. The notochord plays diverse roles in embryonic development. It supports and maintains the shape of embryos, and secrets various inducing factors to affects the patterning of adjacent tissues. Signals emanated from notochord are essential for establishment of left-right asymmetry, formation of the dorsal aorta, specification of the cardiac field, and development of pancreases. In line with its roles of structural support, large amounts of collagen are found around and inside of notochord, which suggests that active protein transport via the secretory pathway is involved in notochord formation. Increases in protein transport occur in cells with active protein synthesis, which on the other hand results in an accumulation of unfolded proteins in the endoplasmic reticulum (ER), a stress condition so-called ER stress. In response to ER stress, cells activate the unfolded protein response to decrease translation and increase protein folding, secretion and degradation in part through activation of the transcription factor XBP1. XBP1 mRNA splicing in cytoplasm requires an endonuclease called IRE1α, which is activated upon ER stress-induced release of the binding of 78-kDa glucose-regulated protein (Grp78/Bip). XBP1 can also up-regulate Grp78/Bip. The functions of XBP1 in the UPR have been studied intensively, yet its roles in embryonic development are largely unknown. We have demonstrated that both XBP1 and Grp78/Bip are preferentially expressed in notochord, and are required for the notochord formation. Knockdown of XBP1 reduced the expression of Sec23 in notochord at tadpole stages. Moreover, gene profiling study revealed a large set of secretory pathway genes are activated in notochord. Therefore, we hypothesize that XBP1 regulates notochord formation through up-regulation of Sec23 to activate vesicle transport in the secretory pathway. We will test our hypotheses as follows: 1) Investigate the transcriptional regulation of Sec23 by XBP1 during notochord development. 2) Investigate molecular mechanisms of XBP1 nuclear translocation. 3) Investigate interactions between XBP1 and Grp78/Bip during notochord formation. By pursuing these lines of study, we can clarify the roles of XBP1 in notochord formation and determine the underlying molecular mechanisms, which will provide more insights into regulatory networks in notochord formation and further our understanding on physiological roles of ER stress during embryonic development. This proposed study will also shed light on novel therapeutic strategies for prevention of birth defects.

Role of TAM receptor tyrosine kinases on blood-testis barrier function and testicular innate immunity

Hong Kong Principal Investigator: Dr. Will M Lee (The University of Hong Kong)
Mainland Principal Investigator: Dr. Daishu Han (Beijing Union Medical College)

Blood-testis barrier (BTB) and testicular innate immune responses play important roles in maintaining the special immune status of the testis. The mechanism underlying the regulation of testicular immunity remains to be clarified. Our groups recently found that TAM (Tyro3, Axl and Mer) receptor tyrosine kinases and Toll-like receptors (TLRs) play important roles in regulating BTB dynamics and innate immunity in the testis. TAM belong to a family of cell adhesion molecule-related receptor tyrosine kinases and they are widely expressed in the testis and most abundantly in Sertoli cells. We propose to examine the role of TAM to coordinate spermatogenesis and immune privilege in the testis using TAM knockout mouse model. Two specific aims will be focused in this proposal: (1) To examine the role of TAM in regulating cell-cell adhesion to maintain BTB integrity and sperm release, and their significance in pathophysiology of the testis; (2) To unravel the function of TAM in maintaining innate immunity and immune privilege status in the testis, and focusing on TAM signaling pathway in regulating TLR-mediated innate immune responses in Sertoli cells. The objective of this proposal is to understand further the mechanism that maintains the immune homeostasis of testis and the BTB integrity for spermatogenesis. This proposal is important since it aims to answer an open question in the field regulating the specific immunological environment in the testis. This study may provide novel clues into the preventive and therapeutic strategies for orchitis-related male infertility.

Novel Functions of Spexin as a Regulator for Reproduction and Feeding in Fish Model.

Hong Kong Principal Investigator: Prof Anderson On-Lam Wong (The University of Hong Kong)
Mainland Principal Investigator: Prof Haoran Lin (Sun Yatsen University)

Neuropeptides are known to play a key role in regulating physiological functions in vertebrates. In 2007, a novel neuropeptide, namely Spexin (SPX), was identified by bioinformatic approach. The mature peptide of SPX was found to be highly conserved among different vertebrates but its biological functions are still unclear. Using goldfish as a model, a pivot study was initiated to examine SPA function in modern-day bony fish. Our results reveal that SPX could suppress LH secretion and feeding behavior in fish model, suggesting that SPX may serve as an inhibitor for reproductive function and energy homeostasis. As a follow-up of these novel findings, research will be initiated to (i) characterize SPX expression in the hypothalamo-pituitary axis and feeding centers within the brain of goldfish to check for possible association with neurons expressing GnRH and other feeding regulators, (ii) elucidate the mechanisms for LH regulation by SPX (direct pituitary actions vs indirect effects within CNS/via steroid feedback) and its subsequent effects on goldfish reproduction, including gonadal maturation, gametogenesis and spawning activity, (iii) establish the functional role of SPX as a satiety factor in goldfish by examining the postprandial changes in SPX expression and SPX modulation of feeding behavior/food intake & brain expression of various feeding regulators, and (iv) prepare synthetic analogs of goldfish SPX and screen for those with agonistic and antagonist activity on gonadal maturation, ovulation and feeding behavior. Our research project not only can enrich our knowledge on SPX function but also have potential applications in induced spawning and appetite control in fish culture.

Interaction study of PinX1 and nucleophosmin and the effect of inhibiting this interaction on tumor growth

Hong Kong Principal Investigator: Prof Pang-chui Shaw(The Chinese University of Hong Kong)
Mainland Principal Investigator: Prof Jun-jian Huang (Academy of Military Medical Science of the PLA)

Cancer is a leading cause of death worldwide. It accounts for 7.6 million deaths in 2008 and this number keeps on increasing. It is projected to rise to over 11 million deaths in 2030. Therefore, an effective approach for cancer therapy is essential. Cellular immortalization was characterized by telomerase activation and telomere maintenance. Over 85% of the immortal cancer cell lines express high level of telomerase and it turns the cells immortal by replenishing the shortening telomere and bypassing the cellular senescence. The present proposal investigates a telomerase regulatory protein PinX1 and its interaction partner nucleophosmin (NPM) for understanding the telomerase regulatory and recruitment pathway. Both overexpression and silencing of PinX1 cause telomere shortening, suggesting PinX1 is an important mediator in telomerase regulation. We have recently identified NPM as a novel PinX1 interacting partner. NPM is usually overexpressed or mutated in cancer cells. We found that NPM/hTERT/PinX1 can form complex inside the cells and NPM can attenuate the PinX1 inhibition on telomerase. To find the contribution of PinX1 and NPM interaction on the telomerase regulatory pathway, we propose to further characterize the model of PinX1/NPM/hTERT complex formation by immunoprecipitation. We shall also determine how PinX1/NPM interaction is involved in the telomerase recruitment. By constructing NPM mutant with defects in PinX1 interaction site and also inhibitory peptides that disrupt PinX1/NPM interaction, we shall find out the biological significance of this interaction in telomere length maintenance of cancer cells as well as tumor growth. Our work will shed light on the role of PinX1 and NPM interaction on telomerase regulation and telomere maintenance. The perturbation of PinX1/NPM interaction may open a new approach in cancer therapy.

Skeletal Role of CK2-interating Protein-1 in Regulating Osteoblastic Bone Formation: Molecular Mechanism and Reversing Osteoporosis

Hong Kong Principal Investigator: Dr. Zhang Ge(Hong Kong Baptist University)
Mainland Principal Investigator: Prof Fuchu He (The Academy of Military Medical Sciences)

The only FDA-approved anabolic agent for stimulating bone formation is parathyroid hormone. However, the dominant bone resorption after 2-year-treatment is a great concern. Thus, it is highly desirable to understand molecular mechanism regulating osteoblastic bone formation and further develop anabolic agents.

Casein kinase-2 interacting protein-1 (CKIP-1) abundantly expressed in skeletal system. C-terminal domain of CKIP-1 can interact with linker between WW domains of Smurf1 and enhance the ligase activity of Smurf1. It is a newly discovered negative regulator of bone formation without activating bone resorption. On the other hand, N-terminal PH domain of CKIP-1 was also required for regulating Smurf1 and CKIP-1 could bind to ubiquitin through the PH domain. In addition, the expression of CKIP-1 increased with aging and bone formation decreased with aging in rodent bone. The identified cross-species CKIP-1 siRNA sequence could promote osteoblast differentiation in vitro and bone formation in healthy rodents. Further, we developed a delivery system (DSS)6-liposome to specifically approach bone formation surface for targeting osteogenic cells in healthy rodents.

An osteoblast-specific Ckip-1 knockout mouse model has been established and it will be characterized for function of CKIP-1 in osteoblast by examining the bone phenotype. The CKIP-1 mutant which lost the ability of ubiquitin binding will be used to determine the role of ubiquitin binding in enhancing the effect of CKIP-1 on Smurf1 activity and osteoblast function. In addition, an osteoporotic mouse model induced by either ovariectomy or orchiectomy will be employed to validate whether (DSS)6 could facilitate organ-/cell-specific delivery and the subsequent cell-specific gene knockdown for bone anabolic action to reverse osteoporosis.

This proposal would help to understand molecular mechanism regulating osteoblastic bone formation and develop RNA interference-based bone anabolic strategy to reverse primary osteoporosis in both male and female.

Analysis of the role of ATOH8 in HCC cancer stem cell and somatic cell reprogramming

Hong Kong Principal Investigator: Prof Xin-Yuan Guan (The University of Hong Kong)
Mainland Principal Investigator: Dr. Tao Wang (Chinese Academy of Sciences)

Hepatocellular carcinoma (HCC) is one of the most common causes of cancer morbidity and mortality in China with extremely poor prognosis. The recent discovery of the role of cancer stem cells (CSCs) in cancer has profoundly altered the landscape of cancer research and changed the way researchers and clinicians view the disease. A better understanding of the characteristics of CSCs would aid in the improvement of more effective cancer therapies against this disease. Our group has identified a CSC population (CD133+) in HCC characterized by their distinctive stem cell properties including abilities of self-renewal, differentiation and tumorigenicity. Recently, we identified a novel candidate tumor suppressor gene ATOH8 in HCC by RNA-seq. Downregulation of ATOH8 can be detected in over 50% of HCCs, which is significantly associated with poorer overall survival (P=0.032) and tumor recurrence (P=0.009) in patients with HCC. Functional assays find that ATOH8 can inhibit the malignant phenotypes of tumor cells such as tumor growth and metastasis. Interestingly, ATOH8 can repress the expression of many stemness-associated genes, such as Oct4, Nanog, CD133 and AFP. We also find that ATOH8 protein possesses an E-box domain apart from the reported bHLH domain. DNA binding motifs for both E-box and bHLH have been detected in promoter region of above mentioned genes. Another interesting finding is that ATOH8 can promote apoptosis and increase the sensitivity of tumor cells to chemotherapeutic agents such as CDDP, 5-FU and doxorubicin. Therefore, we hypothesize that ATOH8 is an important repressor for many of stemness makers, and introduction of ATOH8 into CSCs may induce differentiation and

increase sensitivity of CSCs to chemotherapeutic agents. In this proposal, we plan to investigate effects of ATOH8 on CSCs as follows: 1) to investigate the repressive role of ATOH8 in the regulation of stemness-associated genes; 2) to study whether ATOH8 can increase sensitivity of CSC to chemotherapeutic agents; and 3) to test whether ATOH8 silencing can enhance the generation of induced pluripotent stem cells (iPSCs). The new knowledge gained from this study may reveal the molecular mechanism of CSC's maintenance and develop a novel approach targeting CSCs by increasing their chemo-sensitivity. Knockdown of ATOH8 by RNAi might be applied to enhance or even induce the generation of induced pluripotent stem cells (iPSCs).

Molecular dissection of NSs virulence factor in severe febrile and thrombocytopenic syndrome virus (SFTSV), a novel bunyavirus identified in China

Hong Kong Principal Investigator: Dr. Dong-Yan Jin (The University of Hong Kong)
Mainland Principal Investigator: Prof Mifang Liang (China CDC)

Enhanced surveillance of acute febrile illness in China in recent years has led the Mainland team to the isolation of a novel phlebovirus in the Bunyaviridae family termed severe febrile and thrombocytopenic syndrome (SFTS) virus. This emerging bunyavirus named SFTSV is the cause of SFTS, which was clinically presented with acute fever of >38oC, thrombocytopenia and leucopenia. Some patients rapidly developed multiorgan dysfunction and the case fatality rate was 10-15%. SFTSV is a significant infectious cause of acute febrile illness in China, particularly in the group of patients presented with high fever and thrombocytopenia. The Hong Kong team has a long-standing interest in virus-host interaction and particularly in innate antiviral immunity. In the present study the two teams seek to pool our complementary expertise and resources to jointly derive mechanistic insight into how NSs virulence factor protein of SFTSV perturbs innate IFN response. First, we will fully characterize innate antiviral response in SFTSV-infected cells. Second, a NSs-deficient SFTSV will be constructed by reverse genetics and characterized for virulence and pathogenicity including IFN inducibility. Third, we will verify NSs-mediated inhibition of type I IFN production. Finally, we will shed light on the molecular mechanism of NSs-mediated inhibition of type I IFN production. Our joint work will not only substantially advance the field by providing valuable molecular clones and generating new knowledge about SFTSV pathogenesis, but may also reveal new strategies and targets for developing vaccines and antivirals against SFTSV which remains a significant concern in public health in China.

The Role of the BMP Co-receptor Dragon in Kidney Tubular Development and Regeneration

Hong Kong Principal Investigator : Prof Yin XIA (The Chinese University of Hong Kong)
Mainland Principal Investigator : Prof Baoxue Yang (Peking University)

Kidney disease is a major public health problem affecting about one adult in ten in the general population. Kidney disease can be caused by defective kidney development as well as a variety of insults to adult kidneys. Normal kidney development is dependent on mesenchymal-epithelial interactions in embryonic kidneys. Evidence suggests that BMP4 signaling is critically involved in these reciprocal inductive interactions in both mice and humans. We have recently identified Dragon (also known as repulsive guidance protein b, RGMb), a glycophosphatidylinositol (GPI)-anchored membrane protein, to be the first known BMP co-receptor that enhances BMP4 signaling by increasing the utilization of the BMP type II receptor ActRIIA. Interestingly, our preliminary results show that Dragon is highly expressed in the epithelial cells of ureteric branches, and that Dragon knockout embryonic kidneys at E13.5 showed significant decrease in ureteric branching compared to the wild-type kidneys. We hypothesize that Dragon plays an important role in ureteric branching morphogenesis by facilitating mesenchyme-derived BMP4 signaling in ureteric bud epithelial cells.
Dragon is also expressed in the tubular epithelial cells of adult mouse kidneys. We have now discovered that Dragon expression is highly upregulated in injured tubules in the obstructed kidneys in mice. Importantly, Dragon antagonized epithelial-to-mesenchymal transition (EMT) induced by TGF-£]1 in mouse inner medullary collecting duct epithelial (IMCD3) cells, and promoted tubulogenesis in IMCD3 cells in 3D culture. Taken together, these data suggest that Dragon function may be important in the process of renal tubular degeneration and regeneration.
In this proposal, we will 1) determine the roles of Dragon and the underlying mechanisms in embryonic renal branching morphogenesis in vivo; 2) study the roles of Dragon in renal tubular injury and repair in adult kidneys; 3) examine the mechanisms of the action of Dragon in tubulogenesis in vitro; 4) elucidate the mechanisms by which Dragon enhances the utilization of ActRIIA by BMP4.
This work will improve our understanding of the fundamental mechanisms of kidney tubular development, degeneration and regeneration. The findings could be useful in eventual development of potential new diagnostic and treatment strategies for kidney diseases.

Targeted gene correction and disease modeling using Wilson's disease induced pluripotent stem cells

Hong Kong Principal Investigator : Prof. Hung-Fat Tse (The University of Hong Kong)
Mainland Principal Investigator : Prof Miguel Esteban (Chinese Academy of Sciences)

Wilson's disease (WD) is an inherited liver genetic disorder caused by mutations in ATP7B, which produces a protein responsible for organized copper transport from hepatocytes into blood and bile1. WD leads to copper accumulation throughout the body, which results in varied clinical phenotypes including liver failure and neuropsychiatric manifestations2. However, the correlation between genotype (different ATP7B mutations normally corresponding to different ethnic groups) and phenotype is not well understood. The existing therapies are palliative rather than curative, and are mainly based on copper chelators. Yet, the response to therapies is variable and there are frequent unexpected complications (e.g. fulminant liver failure) that are not well understood either. Unfortunately, the current in-vitro models for WD are largely inadequate and the in-vivo models do not fully recapitulate the course of the disease in patients, and this has hampered research and application.

The generation of induced pluripotent stem cells (iPSCs) from adult somatic cells by over-expression of exogenous transcription factors has become a prominent source of pluripotent cells for biomedical research3. This technique overcomes the ethical issues of using human embryonic stem cells and can be performed in a patient-specific manner. Notably, our recent study4 has shown that functional hepatocyte-like cells (HLCs) derived from human WD-iPSCs reproduce the defect in copper export of WD. In this grant proposal, we want to take full advantage of this model to explore many unanswered questions regarding WD. We also aim to create a preclinical model for testing the possibility of future cell-based therapies for WD using iPSC-derived HLCs.

We will further investigate the genotype-phenotype correlations of WD, for which we will generate genomic integration-free iPSCs from WD patients (Chinese and Caucasian) bearing different ATP7B mutations. Then, we will compare the ability of HLCs derived from these patient-specific iPSCs to export copper upon overload. The pathogenic mechanisms of WD associated with the different ATP7B variants will be further delineated using microarrays, with the hope of detecting signaling pathways whose modulation might improve the clinical course. Moreover, using the recent advances in technology on combining zinc finger nuclease5 with the piggyBac for homologous recombination, we will generate genetically corrected iPSC-derived HLCs for transplantation in a mice model of WD. Taken together, our project will potentially lead to new insight in the disease mechanism as well as the development of novel therapies for WD.

Pharmaceuticals in Municipal Sewage Treatment Works of China: Behaviour and Risk Assessment

Hong Kong Principal Investigator: Prof Paul Kwan-sing Lam(City University of Hong Kong)
Mainland Principal Investigator: Prof Hanqing Yu (University of Science and Technology of China)

Pharmaceuticals, which are widely used in our daily life for the protection of human and animal health, have recently been regarded as contaminants of emerging concern. Pharmaceuticals have been ubiquitously detected in aquatic compartments such as seawater, river water and even groundwater. Municipal sewage is one of the main routes by which pharmaceuticals are conveyed into the aquatic environment. The presence of these bioactive compounds in the effluent of sewage treatment works (STWs) has been extensively reported in European and American countries. Recently, extremely high levels of pharmaceuticals were reported in effluents in India which has raised environmental concerns about the current situation in developing countries. For instances, even in trace amount, these bioactive compounds may lead to endocrine disruption in intact organisms and also cause a potential increase in bacterial resistance.

Due to the potential risks arising from intrinsic biological effects attributed to the continual discharge of pharmaceuticals into water bodies, the prevention of these chemicals into the aquatic ecosystem is of utmost importance. STWs act as a barrier for micro-pollutants (including pharmaceuticals) and prevent the infusion of potentially harmful substances into the aquatic environment, however, although some pharmaceuticals can be degraded during sewage treatment processes, a considerable amount of residues (non-decomposed portion) are still found in the effluents which eventually contaminate the environment. To date, different sewage treatment technologies are adopted; and among them, conventional activated sludge treatment (CAST) is the most common process used in China for treating municipal wastewater. Therefore, whether or not pharmaceuticals can be eliminated in the STWs from China essentially depends on the removal efficiency of the biological treatment process.

In CAST, microorganisms, especially bacteria, play an important role in the removal of trace organics from wastewater. Non-metabolized pharmaceuticals such as antibiotics may have the potential to negatively impact the microbial community in biological sewage treatment systems and thus lower the overall elimination efficiencies of nutrients and micro-pollutants by inhibition of activated sludge bacteria. This study, therefore, proposes to (1) investigate the fate and distribution of a wide-range of pharmaceuticals in STWs from Hong Kong and Shanghai where the conventional activated sludge treatment process is widely utilized to treat municipal wastewater; and (2) to compare the removal efficiencies among different wastewater treatment processes. Furthermore, (3) key biological factors determining the elimination efficiencies of pharmaceuticals in activated sludge process will be identified by evaluating the effects of pharmaceuticals on microorganisms commonly found in wastewater.

Electromigration and Thermomigration Studies in Nanostructured Composite Electronic Interconnects for Nanoelectronics Applications

Hong Kong Principal Investigator: Prof. Yan-Cheong Chan (City University of Hong Kong)
Mainland Principal Investigator: Prof. Fengshun Wu (Huazhong University of Science and Technology)

There is a continuing trend of miniaturization in the evolution of electronics - towards higher packing densities for the components that form integrated circuits, circuit-boards and sub-systems. Higher component packing density provides improved performance in terms of speed, power consumption and space occupied - together with lower cost. Electronic packaging engineers face the challenges of achieving better individual component reliability at higher power densities with consequently greater electrical and mechanical stress levels and the vital need to dissipate waste heat effectively. There is no way to solve future problems except with an increasing the knowledge-base for lead-free interconnect through in-depth understanding of all interacting failure mechanisms. Novel materials are needed that can overcome the challenges of stability and robustness - and avoid the classic failure mechanisms of electromigration (EM) and thermomigration (TM) - where thin films degrade through the transport of metal atoms to produce many millions of microscopic breaks between the microscopic metal grains that form the conductor. The advanced nanoscience or nanotechnology especially novel nanostructured composite materials are essential to incorporate the interconnecting tracks on advanced electronic packaging and to replace the conventional interconnect materials that are frequently used in electronic components.
Novel nanostructured composite electronic interconnects with highly conductive reinforcements i.e., nano-ceramic particles, nano-multilayer graphene etc. and dielectric solder matrices will be soon replaced the conventional electronic interconnects. A key ingredient in the creation of novel nanostructured electronic interconnect is the use of highly conductive functionalized nano-metallic coated nano-ceramic particles that are only a few nanometers in diameter - or the functionalized nano-metallic coated novel alternative of precisely deposited and shaped graphene multi-layers. In the proposed project, nanostructured composite interconnects will be prepared by addition of highly conductive functionalized nano-reinforcements and synthesis lead-free nano solder paste and developed an innovative 3-D theoretical model to predict the life time of nanostructured composite electronic interconnects. EM and TM-induced failure mechanisms with under-bump-metallization dissolution, intermetallic compound formation, current crowding, void formation, thermo-mechanical behavior and plastic flow of nanostructured composite interconnects under the combination of all the incorporating interacting loads (electro-thermo-mechanical- chemical) will be investigated using a Physics-of-Failure (PoF) approach. The Physics-of -Failure approach coupled with carefully Design-of-Experiment (DoE) will revolutionize the EM and TM-induced failure phenomena of nanostructured composite electronic interconnects and providing a strong foundation for a better scientific understanding of the capabilities and limitation of such physical phenomena in next generation advanced nanoelectronics applications.

Mathematical Modeling and High Performance Computing of Complex Fluids

Hong Kong Principal Investigator: Prof Tao Tang (Hong Kong Baptist University)
Mainland Principal Investigator: Prof Li Yuan (Chinese Academy of Sciences)

This research project aims at the development, analysis and computer implementation of mathematical models of complex fluids. The study of structure and dynamics of complex fluids plays an important role in understanding the most relevant problems in physics, chemistry, biology, and engineering. Physical phenomena occurring at different length scales can be strongly correlated, giving rise to complex fluid-structure interaction problems. The mathematical analysis of these problems is complicated and the related numerical analysis is difficult.

In this proposal, we propose to combine the recently achieved theoretical results on complex fluids and numerical schemes for solving large scale problems to solve multi-dimensional complex fluid problems including flows of liquid crystal polymers, multiphase complex fluids, and complex bio-fluids etc. Modern numerical techniques such as high performance computing, adaptive fluid-flow computation, CPU-GPU hybrid computing will be developed. The numerical simulation results will be compared with the existing experimental results, which are mostly with complicated geometry or multi-dimensions. Our purpose is to set up a mathematical simulation platform eventually leading to a better understanding of many challenging theoretical and computational issues relevant to complex fluid problems.

Development of Novel Organoboron Chromophores for Two-Photon Cell Imaging

Hong Kong Principal Investigator : Prof Dennis K P Ng(The Chinese University of Hong Kong)
Mainland Principal Investigator : Prof Guoqiang Yang (Institute of Chemistry, Chinese Academy of Sciences)

Two-photon absorption is a third-order nonlinear optical process in which an electronic transition occurs from the ground state to an excited state upon simultaneous absorption of two photons of half energy from an intense laser source. With the advance of laser technology, this phenomenon can be readily observed which has greatly facilitated the studies of two-photon-absorbing materials. Two-photon excitation can lead to higher spatial resolution, and the use of longer-wavelength radiation enables deeper light penetration into scattering media. These advantageous properties render these materials to find important applications in various disciplines, such as three-dimensional optical data storage, lithographic microfabrication, two-photon fluorescence imaging, and two-photon photodynamic therapy. As a result, there has been considerable interest in development of novel and efficient two-photon-absorbing chromophores. The aim of this proposal is to combine the strengths of both the Hong Kong and Mainland researchers to develop novel organoboron chromophores, including boron dipyrromethenes and their aza analogues for two-photon cell imaging and photodynamic therapy. These compounds are highly versatile functional dyes showing high fluorescence quantum yields, tunable photophysical properties, and good solubility and stability in many solvent systems. Their strong near-infrared absorptions also make them well suited for biological applications. However, there has been little study on their two-photon absorption and emission properties. In this project, we will design, synthesize, and characterize a series of these compounds having strong electron-donating or withdrawing groups attached to the π skeleton. It is expected that these moieties can promote the intramolecular charge-transfer character of these compounds, thereby enhancing their two-photon absorption cross sections. Emphasis will be placed on the amphiphilic analogues which generally have higher cellular uptake. The photophysical properties of these compounds, both under one-photon and two-photon excitation, will then be examined with focus on the structure-property relationships. Finally, their potential as selective fluorescent probes for two-photon cell imaging and as efficient photosensitizers for two-photon photodynamic therapy will be evaluated.

High Performance Resistive Phase Change Memory Technology for Terascale Storage

Hong Kong Principal Investigator: Prof. Mansun Chan (The Hong Kong University of Science & Technology)
Mainland Principal Investigator: Prof. Zhitang Song (Chinese Academy of Science)

The recent growth of the consumer multimedia market has generated a strong demand for compact and high-density solid-state non-volatile memory. The trend has been accelerated with the growth of the popularity of high quality video applications. The mainstream non-volatile memory technology is dominated by capacitive type storage such as floating gate EEPROM and FLASH. However, due to the increasing difficulty to further scale capacitive type memories to increase its storage density, there is a strong demand to change the core technology to extend the scaling process. As a result, resistive type of memory has gained a lot of attention recently due to its advantages of high density, simple structure and fast read/program time. The most promising technology for resistive memory is the Phase Change Memory (PCM) which consists of an ovonic material like Ge2Sb2Te5 (GST) which has two different resistance values corresponding to high resistance (amorphous) and low resistance (crystalline) states. The switching between the two states can be achieved by controlling the amplitude and duration of Joule heating cycles resulting from a current pulse applied to the cell. To program the material to the high resistance state, the ovonic material is heated to a temperature above the melting point and quenched very quickly. The final resistance depends on the temperature profile during quenching. To program the material to the low resistive state, it is heated to a temperature above the glass transition point for an extended period of time (but still within the -second range) and the quenching time is less important. While the concept of PCM has been demonstrated, the manufacturing of high performance and reliable PCM combining mainstream nanometric CMOS remains difficult.
Even though PCM technology is more mature and promising than other resistive memory based technology such as RRAM, there are still a number of problems to resolve, with the most critical ones being: (1) lack of understanding on the material properties that correspond to various output characteristics; (2) high current required to perform RESET with unoptimized structures; (3) lack of a detailed model for predicting interaction between the PCM cell and the driving circuits; (4) a methodology for studying reliability issues including thermal cross-talk and data retention. Therefore, PCM has remained in the state of prototyping and experimental demonstration by large companies like Samsung and IBM. No large-scale consumer products have been released in the consumer market yet. In this project, we are going to address the four major problems described above to allow a deeper understanding of the PCM technology. Based on the understanding obtained in this work, we are going to study the methodology of PCM cell design and demonstrate a methodology to fabricate high density three-dimensional stacked memory array, which is the ultimate goal in memory architecture.

Study of structure, interface and property modification of metal-cluster-decorated graphitic nanostructures

Hong Kong Principal Investigator: Prof Ning Wang (The Hong Kong University of Science & Technology)
Mainland Principal Investigator: Prof Dang-Sheng Su (Chinese Academy of Sciences)

Having high aspect ratios, huge surface areas and high thermal stability, graphitic nanostructures are ideal supports of atomic clusters for making functional nanostructures. To functionalize graphitic nanostructures, bio-molecules, chemical groups or metal clusters are often attached to their surfaces. For metal cluster decoration, the structurally or chemically induced defects often change the metal-carbon interaction and thus the electrical and chemical properties of graphitic nanostructures. In this project, we propose to systematically study the metal cluster surface and interface structures and their interaction with graphitic nanomaterial surfaces. We'll investigate the defect structures induced by chemical doping and their modification of the properties of graphitic nanostructures. We will elucidate the relationship between structure and property modification for metal-cluster-decorated and element-doped graphitic nanostructures. The results are highly relevant to fabricating efficient nano graphitic composites for technological applications in many areas.

Design of high performance organic solar cell structures with newly proposed polymer materials to beyond 10% efficiency

Hong Kong Principal Investigator: Dr. Wallace C.H. Choy (The University of Hong Kong)
Mainland Principal Investigator: Dr. Lijun Huo (Chinese Academy of Sciences)

Organic solar cells (OSCs) with polymer-fullerene bulk-heterojunction active layers have been considered as a promising candidate for photovoltaics due to their interesting features (e.g. low cost, low temperature fabrication, mechanical flexibility, etc). As compared to conventional semiconductor thin-film solar cells, the power conversion efficiency (PCE) of OSCs is generally low. In order to increase OSC performances and PCE beyond 10%, we will study different aspects of OSCs including polymer donors of active layer, light trapping structures, charge transport layers (CTLs) and transparent electrodes.

Based on our recently invented benzo[1,2-b:4,5-b']difuran (BDF) building block, we will synthesize a new series of polymer donors and pay particularly attention to small bandgap materials with strong light absorption for extending the absorption wavelength region and thus increasing short-circuit current (Jsc). Meanwhile, we will further reduce the highest occupied molecular orbital (HOMO) of polymer donors so that turn-on voltage (Voc) can be increased. For effectively transferring photogenerated carriers to electrodes, we will improve the hole mobility of polymer donors.

One of the main challenges of OSCs is to achieve physically thin and optically thick active layer for allowing efficient carrier generation and collection without weakening light absorption. We will address this issue by proposing double plasmonic structures. Plasmonic resonances offer very strong near fields which can increase light absorption in active region. By introducing double plasmonic structures, we aim for achieving a wide range of absorption enhancement.

It is important to extract photogenerated carriers to electrodes. Generally, good metal-oxide-based CTLs need high temperature annealing of 200-300 degC, we will investigate new low-temperature solution-processed metal oxides. We will also investigate methods to further improve the electrical properties of CTLs.

Indium tin oxide (ITO) is a common electrode with good conductivity and transparency. Its brittle feature makes ITO has some concerns for uses in flexible organic optoelectronics. We propose to develop a composite of graphene based materials for flexible and transparent electrodes. We will optimize the graphene based materials for high performance OSCs.

Through the detailed studies from materials to device structures, we will contribute to not only better understanding OSCs but also realizing OSCs with PCE over 10%.

Mathematical Theories of Some Kinetic and Fluid Models

Hong Kong Principal Investigator: Prof Tong Yang (City University of Hong Kong)
Mainland Principal Investigator: Prof Huijiang Zhao (Wuhan University)

To study the gas and fluid dynamics, many famous equations have been derived in different physical scales and some of them can be traced back to 19th century or earlier. These systems of equations not only build up the foundation of physics, but also provide mathematicians many challenging mathematical problems.

In the macroscopic scale where the gas and fluid are regarded as continua, the systems of Euler and Navier-Stokes equations are the most famous systems which still attract a lot of attentions in establishing their well-posedness theories in mathematics.

In the contrary to the macroscopic scale, that is, in the microscopic scale, the gas and fluid are viewed as a many-body system consisting of microscopic particles (atom/molecule), where the motion of the system is governed by a system of coupled Newton equations. Although the Newton equation is the first principle of the classical mechanics, solving such system of enormous coupled equations is not practical. Based on the fact that the macroscopic quantities are the statistical average of quantities depending on the microscopic state, the kinetic theory that gives the mesoscopic description of the gas and fluid is a bridge between the microscopic and macroscopic scales. In this regard, the most classical and fundamental kinetic equation is the Boltzmann equation derived in 1872.

In this project, we will focus on the following four problems: the well-posedness theories for some complex kinetic equations, such as the Vlasov-Maxwell-Landau (Boltzmann) systems which are among the most fundamental systems in kinetic theory; the exterior problems for kinetic equations without Grad's angular cut-off assumption; the formation of patterns and propagation of singularities; and the global solutions to some fluid and kinetic models with large initial data. Note that the study on these problems is in the frontier of the research in the fields of kinetic equations and fluid dynamics because they not only have strong physical background and but also have challenging mathematical difficulties. We expect the progress in solving these problems will not only enrich the mathematical theories in the area, but also shed some light on the explanation of the related physical phenomena.

Dynamical Network mechanisms of information processing in neural systems

Hong Kong Principal Investigator: Prof Michael K Y Wong (The Hong Kong University of Science & Technology)
Mainland Principal Investigator: Prof Si Wu (Beijing Normal University)

The brain is a complex information processor. Understanding the mechanisms of information processing in neural systems is not only the key for us to elucidate higher cognitive functions, but is also the foundation for us to develop artificial intelligence. In this project, based on the experimental data, we aim to use mathematical approaches and models, in particular those for analysing network dynamics, to investigate several key issues concerning the strategies of neural systems in processing dynamical information. These issues are: 1) how short-term plasticity among the synapses of neurons affects the dynamical behaviors of the neuronal network, and hence assists the neural system to process motion information; 2) how positive and negative feedbacks among the different layers of neural circuit modulate the network responses to external inputs, and what computational capabilities they carry; 3) how scale-free neuronal networks encode and store external temporal information; 4) how hierarchical modular neuronal networks maintain local criticality and global stability, and hence optimize their computational capacities.The project involves four researchers with many years of experience in neurodynamics research. The PIs from Mainland and Hong Kong have a long history of successful collaborations. The researchers (PIs and Co-IIs) have their individual strengths and complementary expertise, favouring the successful completion of this multidisciplinary project.