Research Fields
Primate Genetic Diversity and Diseases Pathogenesis
1. Genomic diversity of primate laboratory animals
The correlation analysis between genomic diversity and phenotypes usually gives a hint to susceptibility for human diseases. Since humans and rhesus monkeys share conserved causative genes for diseases and conserved receptors for drugs, meaningful information can be achieved from a direct comparison between humans and monkeys on variation of gene sequence and structure, polymorphism in non-coding RNA, as well as diversity of epigenetic modification. The findings of systematical studies on these aspects will allow us to further understand the phenotypic diversity of complicated human diseases, and offer clinical suggestions for personalised medicine.
2. Polymorphisms on gene sequence - the underlying genetic basis for individual difference on drug response
Increasing clinical evidence has shown that patients diagnosed with the same disease exhibit different responses to the same medicine. Although it has been suggested that the different side-effects and responses to the medicine is largely attributed to the sequence polymorphism of drug target site and metabolic enzyme among individuals, systematical studies are still needed. The sequence polymorphism in NHPs supplies us an opportunity to conduct such studies and the findings will inspires the clinic personalised medicine greatly.
3. Unique mutations in genome - the underlying genetic basis for human complicated diseases
Extensive Genome Wide Association Studies (GWAS) have been performed among population so far. However, only a few complicated diseases have been associated with known genes. The causative mutation in the vast majority of cases, especially those with neurodegenerative diseases, remain unrevealed. Recent studies have shown that the rare mutations including copy number variants (CNV) could be the vital genetic basis for human complicated diseases, although they have not been given enough attention before. The polymorphism of NHP genome makes it an ideal model for research on rare mutations.
4. Pathology and molecular therapeutic target
We are performing researches on genetic mechanisms underlying human diseases using rhesus monkeys as a model organism. We aim to promote the translation of all the verified findings and techniques in NHP researches into clinical practice. We are also interested in developing genome-based diagnostic applications, which might indicate the direct association of mutations with human diseases and inspire new therapeutic targets.
NHP models for complicated human diseases
1. Optimisation of genome-editing tools
Targeted genome modification technologies, including CRISPR/Cas9 and TALENs system, open up a vast prospects for diseases therapy. In both these two approaches, upon site-specific DNA recognition and cleavage, insertions and/or deletions (indels) can be induced, resulting in disruption of the targeted locus.Alternatively, knock-in of interesting fragment can be made if a donor template with homology to the targeted locus is supplied. However, systematical verification and optimisation are still needed before these techs can be eventually applied in clinic. Using NHP models, we are interested in optimising these genome-editing tools with high efficiency and low off-target effects, as well as a precise knock-in method which has not been achieved in NHP animals.
2. NHP models for complicated diseases
We are generating gene modified monkey models for a spectrum of aging related complicated conditions, including neurodegenerative diseases, metabolic diseases, and infectious diseases. Taking advantage of these NHP models, we are interested in understanding the etiology and pathology of human complicated diseases, anddifferentiatingthe contribution of geneticfactors versus environmental factors during occurrence of diseases. We are also interested in looking for biomarkers which could help with early detection and diagnosisof diseases, as well as therapeutic targets which may have potential to delay disease progression or cure diseases. Finally, these gene modified monkeys are also invaluable resources for preclinical studies on the safety and efficacy of biotherapies.
3. Safety assessment for biotherapies
We are working on the safety assessment for biological therapies, especially those based on stem cell treatment or gene modification. Different types of stem cellsor terminally differentiated cells will be used for stem cell treatment, andcomparative studies will be carried out between human-derived cells and monkey-derived cellstreatments,as well asautologous and allogeneic cell transplantation therapies. Howtransplanted cells survival, differentiation, migration, and functional reconstruction are still largely unknown. A controversy remains regarding the tumor and dysfunction caused by transplanted cells in vivo. the corresponding cells and other functional problems, achieving the regeneration and repair of transplanted cells. And functional reconstruction to obtain data on the safety and efficacy of stem cells for disease treatment. Use the CRISPR/Cas9 system or TALENs targeted gene editing technology to repair the disease-causing genes in vitro, and differentiate the repaired cells into specific types of nerve cells, and then transplant them to animal models of primates (the use of monkey cells). Autologous transplantation methods) to investigate the safety and efficacy of stem cell gene modification therapy.
Research Team
Primate Stem Cell and Tissue Engineering
1.Early embryo development and lineage differentiation
Early embryonic development and cell lineage differentiation creates an applicable extracorporal embryo deferred culture system for primates, and combines extracorporal culture system and inserting technique mediated by targeting gene editing method, to realize visual tracking to triploblastic cells during their gastrula stage, in order to solve the technical and material issue on cell lineage research in the early phase. We analyse special transcriptome, epigenetic feature, transcription factors and signalling pathways regulatory networks during the establishment of primate cell lineage. We use gene editing technique to do researches on early lineage key signalling pathway and epigenome modification, to reveal the pathogenic mechanism of early developmental diseases, and offer a foundational concept for related prevention and treatment to early developmental diseases.
2.Stem cell pluripotency and tissue engineering
We are establishing primate (including human) naive stem cell lines with chimera competent and germline competent,and verifying whether these naive stem cells can produce chimeras by tetraploid compensation. Based on these work, we are planing to reveal the unique molecular markers for naive stem cells, as well as the molecular mechanisms underlying the naivety. The findingwill serve as an important reference for the standardized culture of pluripotent stem cells. At the same time, human naïve stem cells were transplanted into monkeys for safety assessment. Giving the ability of producing chimeras for naive stem cells in vivo.
3.Stem cell preparation and scale culture
Through stem cell preparation and scale-up culturing, we build a serum-free, well-defined culture medium and culture system for isolating and culturing primate stem cells. Based on this, we also developed large-scale culturing (three-dimensional) technology for primate stem cells, completed 500 ML - 1L scale expansion, and created a stable, continuous, pollution-avoidable scale expanding system. Cell production has reached more than1x106 per ml, and adult stem cells production has been amplified more than 10,000 times compared with the original generation, with cell function maintained. Besides, we established a real-time monitoring and managing system for expanded stem cells to obtain stable, homogeneous stem cell products. To develop techniques and systems for the directed induction of differentiation of stem cells into functional, high-purity, and homogenized specific tissue cells.
4.Application of biological materials in stem cell transformation
Application of Biomaterials in Stem Cell Transformation involves a variety of synthetic or natural macromolecular substances with good biocompatibility, extracellular matrix-like bioactive substances with cell-mediated differentiation functions, and nanomaterials or biomaterials that are conducive to cell differentiation. By researching on the interactions between stem cells, extracellular matrix, biomaterials, and active molecules, we are to identify the role of biological materials in cell growth and differentiation, and to screen out biological materials which are suitable for stem cell growth and differentiation. By transplanting cells, obtained by three-dimensional and two-dimensional culture and differentiation, into a monkey disease model, we are to study the fate of those cells, ie, cell integration, migration, differentiation, and the differences of functional connection with the host cells, in order to promote the application of biological materials in stem cell transformation.