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ANR/RGC Joint Research Scheme - Layman Summaries of Projects Funded in 2014/15 Exercise

Refining the bioactivity of P42, a hit therapeutic peptide, and developing a combined therapeutic peptide approach for treating Huntington's Disease

Hong Kong Principal Investigator: Dr Edwin Ho-yin Chan (The Chinese University of Hong Kong)
Mainland Principal Investigator: Dr Florence Maschat (University of Montpellier 2)

Huntington's Disease (HD) is caused by a DNA repeating unit expansion mutation in the human genome. This deleterious mutation causes nerve cell death in the brain and gives rise to HD symptoms including movement disability. In 2013, our team identified a potential peptide-based therapeutic agent that can effectively correct the motor defects in HD disease mice. The major aims of the proposed work are (1) to optimize the bioactivities of the therapeutic agent using peptide engineering techniques, and (2) to develop efficient peptide delivery system to deliver the agents to the brain of HD disease mouse model. In the long run, our work will open up new therapeutic options for HD.

Molecular regulation of muscle stem cell aging by canonical Wnt signaling

Hong Kong Principal Investigator: Prof Hiu Tung Tom Cheung (The Hong Kong University of Science and Technology)
Mainland Principal Investigator: Dr Fabien Le Grand (Cochin Institute)

The increased lifespan of the population in developed countries poses a number of issues related to the health control and social assistance in elderly population. For instance, an increased incidence of age- associated muscular diseases, such as progressive atrophy (sarcopenia), lead to a drastic worsening of lifestyle in aged people and to increasing request for medical and social assistance. Our knowledge of biological aging is limited and it is thus crucial to achieve a better understanding of how we can improve health and longevity. Previous reports have suggested that the decline in functionality in aged tissues are linked to cellular aging of somatic stem cells, which are altered and loose their function. Therefore, understanding the molecular mechanisms by which muscle stem cells undergo cell fate decisions is of key importance to design new experimental therapeutic strategies to promote muscle tissue repair.

The canonical Wnt cascade is a critical regulator of stem cells biology in many adult tissues. Our previous work highlighted that many Wnt proteins are secreted during muscle regeneration and specifically that non-canonical Wnt7a signals controls MuSC self-renewal. We recently observed that an adequate level of intrinsic canonical Wnt/ß-Catenin signaling in MuSC is necessary for their function during tissue repair and strikingly that ß-Catenin target genes were misregulated in old MuSCs. We hence hypothesize that modulation of canonical Wnt/ß-Catenin signals in vivo during MuSC aging may lead to improvement of skeletal muscle homeostasis and allow the design of new strategies against skeletal myopathies and sarcopenia. Out project aims to understand how deregulation of pathways such as Wnt signaling accounts for physiological and pathological skeletal muscle tissue ageing.

Assembly and dynamics of active and passive micro-ellipsoids at a fluid interface

Hong Kong Principal Investigator: Prof Yilong Han (The Hong Kong University of Science and Technology)
Mainland Principal Investigator: Prof Maurizio Nobili (Universite Montpellier 2)

Predicting the physical behaviour of particles at fluid interfaces is crucial for the design and optimisation of many industrial processes ranging from the stabilization of emulsions in the food and pharmaceutical industries to the flotation techniques applied in wastewater treatment and mining. All such applications demand a better knowledge of the particle dynamics and interactions at the interface. In the past the scientific focus has been restricted to spherical particles with few studies devoting to the more realistic anisotropic particles.

This proposal focuses on both passive and active anisotropic micrometric particles (ellipsoids and elliptical platelets) designed and fabricated in the laboratories of the consortium. Such particles capture the essential physics related to the anisotropy. We propose to elucidate for the first time the coupled dynamics of a single ellipsoid close to or at a fluid interface and the two-dimensional collective behaviour of ellipsoids confined to such interfaces. A novel integrated optical set-up capable of manipulating and tracking the three-dimensional position and orientation of the ellipsoids will be developed. In addition, our novel high sensitivity force microprobe based on atomic force microscopy will be further enhanced with the capability to access capillary and active forces acting on such particles and their fluctuations. The interactions among ellipsoids will be addressed by carefully adjusting the capillary energy around the thermal energy level. When the strength of the capillary interaction is comparable to those of other interactions, their competition will give access to a large variety of patterns and coupled phenomena. The capillary interaction will be controlled by changing the wettability of the particles, the surface tension of the fluid interface and the aspect ratio of ellipsoids, adding magnetic dipolar repulsions and making self-propelled ellipsoids.

Monolayer ellipsoids at fluid interfaces exhibit rich phase behaviours, and can serve as model systems for the study of phase transitions in two dimensions at single-particle resolution by video microscopy. Compared with the conventional systems of repulsive colloidal spheres, ellipsoids with an anisotropic shape and tuneable attractions can better mimic molecules. The measurement of their rotational motion further facilitates the study of the important roles played by such motions in phase transitions, which have not been carefully examined previously. We will experimentally investigate some of the most important unsolved problems in physics, including the predictions of Kosterlitz-Thouless about two-dimensional isotropic-nematic transitions, the frustration and dynamics in rotator phase and glass transitions.

A novel PD1 DNA-based vaccination strategy to mimic Gag-specific responses found in HIV Elite Controllers

Hong Kong Principal Investigator: Dr Zhiwei Chen (The University of Hong Kong)
Mainland Principal Investigator: Dr Lisa Chakrabarti (Pasteur Institute)

This project aims at developing an innovative DNA vaccination strategy against HIV. The development of an effective HIV vaccine represents a major public health objective, as HIV remains one of the most devastating infectious agents, with over 35 million people currently living with the virus worldwide (UNAIDS 2013). Our groups (teams FR1 and FR2) have shown that some rare patients recruited by team FR3, called HIV Elite Controllers (ECs), develop T cell responses that are particularly efficient at sensing low amounts of virus and at eliminating infected cells. Developing a vaccine that induces Gag responses similar to those seen in Controllers represents a key objective of this project. Using techniques developed by FR teams, we will focus on a novel sPD1-Gag DNA/EP DNA vaccination platform, discovered by team HK1, that was shown to induce high frequency, high-sensitivity, and persistent Gag responses by using the TERESA electroporation (EP) device provided by our industrial partner (team HK2) for in vivo DNA vaccine delivery. The most promising strategy will then be evaluated in a SIVmac239/macaque model by team HK3. We will use the responses measured in HIV or SIV ECs as a benchmark for optimal vaccine responses. These experiments will provide preclinical data to support a future trial of the sPD1-Gag DNA/EP vaccine in humans.

Pattern formation by bacteria: from theoretical physics to synthetic biology

Hong Kong Principal Investigator: Dr Jiandong Huang (The University of Hong Kong)
Mainland Principal Investigator: Dr Julien Tailleur (Université Paris Diderot)

How biological structures or patterns are formed is one of the most fundamental questions in modern science. It involves intriguing processes and has been a recurrent topic that fascinated generations of scientists. However, the underlying determinants are often buried in the overwhelmingly complex context so that a unified picture has yet to emerge. Most approaches in the field are indeed limited to one specific viewpoint. It is our perception that further significant progress requires both linking the microscopic dynamics of individual cells to the macroscopic formation of biological structures, and accounting for the physical and biological aspects of cell motion and cell-cell interactions. This project proposes to build such an integrative approach by combining theoretical and experimental physics-to model and characterize accurately biological pattern forming systems-and synthetic biology-which opens up the possibility to control cell behavior through the design of specific genetic circuits. We will bridge the gap between theoretical and experimental, physics-based and biology-based, approaches of pattern formation to understand and control the pattern formation process. We will use these systems to study how the underlying cell-cell interactions can lead to cell-sorting, interplay with genotypic segregation, and affect the population dynamics of multi-species systems. The successful completion of this project will be possible thanks to the complementarities of the French and Hong-Kong teams, gathering in the same project expertise in experimental physics, mathematical modeling and synthetic biology. This synergy, much needed to make substantial progress in the field of pattern formation, will also strengthen both teams and countries on the long term, thanks to the technological transfer between the partners.