复旦大学发育生物学研究所

psychology

复旦大学发育生物学研究所
                              复旦大学发育生物学研究所


The Institute of Developmental Biology and Molecular Medicine (IDM) is an international biomedical research center. The IDM was funded by Fudan University and was further supported by the Science and Technology Commission of Shanghai Municipality and other funding agencies including the National Natural Science Foundation of China (NSFC). Its laboratory was first opened in Feb. 2002. The IDM pursues broad biomedical researches with a strong effort in the area of developmental biology and molecular mechanisms of human diseases. The IDM offers competitive training programs for highly motivated trainees at both graduate and post graduate levels. As an international academic research center, the IDM promotes scientific and educational exchanges with international scholars. The IDM works closely with the School of Life Science, Fudan University and the Morgan-Tan International Center for Life Sciences in building scientific and academic excellence in China.



Research Interests
The striking gene conservation between humans and model organisms such as mice, the fruit flies, Drosophila melanogaster, and the nemetode worms, C. elegans, provide a unique opportunity to study gene functions in model organisms. The ability to make crosses between genetically defined strains under controlled environment conditions, to work with large sample sizes, to generate transgenic and knockout animals with mutations in specific genes provide these animal models with powerful genetics. Combining the genetics with the enriched knowledge of the developmental biology in these model organisms, research in these animals has contributed and will still provide the majority of our current knowledge of gene functions and modern biology.

IDM uses multiple model organisms including mouse, fruit fly, and soil worm to study a number of important biological problems related to animal development and human diseases. We are particularly interested in the mechanisms of animal size control, tumorigenesis and metastasis, neural degeneration, and developmental pattern formation. We are also developing new genetic tools in mouse to facilitate functional genomic analysis.

Systematic Analysis of Human Gene Functions in Transgenic Animals

The human genome sequence has been determined. The current challenge is to understand the functions of the genes encoded by the human genome. One of the most powerful ways to reveal gene functions is genetically alternating genes in organisms and observing the phenotypic consequences. Genetic organisms such as mouse, Drosophila melanogaster, and C. elegans, are some of the most powerful models for large-scale genetic manipulations.

We are currently utilizing Drosophila and mouse to perform large-scale functional genomic studies in our institute. The first step of this research is to probe functions of human genes or their homologues by a systematic overexpression screen. The advantages of Drosophila genetics allow us to get the functional clues fairly efficiently. Following the leads from the screen results, genetic and biochemical analyses including generating transgenic, and in some cases gene knock-out mice are being or will be carried out to study the functions of the selected genesc. With this strategy, we have currently finished screening more than 300 human genes, and got dozens of positive results. Several animal models of common human diseases have also been developed.


Cell and Animal Size Regulation

Size is one of the most obvious characters of different species. Recently, many oncogenes and tumor suppressor genes have been found to be involved in cell or organism size control, suggesting that the size regulatory mechanisms also play critical roles in disease processes such as tumorigenesis that require increases in tissue size.

In Drosophila and in mammals, the Insulin/PTEN/TSC signaling pathway and the ras signaling pathway are two major players in cell size regulation. In mammals, these two pathways are known to be involved in various important developmental and disease processes, such as tumorigenesis. It is thus important to identify new factors that act in or with these pathways to regulate cell and animal sizes. Among many candidate genes we have identified through the overexpression screens, one was identified to be a component of the translation machinery. The characterizaition of this gene by a student indicate that it acts downstream of a known size control mechanism in Drosophila.

In addition, we have generated transgenic and knock-out mice for several components of the Insulin/PTEN/TSC as well as other evolutionarily conserved tumor suppressor genes such as lats. These mutants are now being studied to explore the relationship between size control mechanism and tumorigenesis in mammal.


Regulation of Ras Signaling Pathways

The Ras-mediated signaling pathways are involved in many critical cellular events including cell proliferation and differentiation. Multiple model organisms are being used to study certain regulatory aspects of this pathway. We have generated knockout mouse of the sur-8 gene that plays critical role in regulating the activation of Raf kinase by Ras. Preliminary results indicate that the gene is essential for mouse development. We are also cloning and characterizing a previously unknown gene that negatively regulates Ras/MAP kinase signaling activity in C. elegans. Biochemical and mouse genetics work will immediately follow once the worm gene is fully characterized. In addition, chemical genetic method will be explored to discover new means to suppress the activity of this signaling pathway.


Metastasis

Metastasis is the major cause of mortality for cancer patients. Given that the genetic alterations that cause metastasis are usually late events and that multiple genetic alterations occur in late stage cancers, traditional approaches have not been fruitful in identifying genes involved in metastasis. Professor Xu has designed a genetic screen in Drosophila to interrogate the genome for mutations that can cause otherwise noninvasive tumors of the eye disc to exhibit metastatic behaviors, such as the invasion of neighboring or distant tissues. We are systematically interrogating the Drosophila genome to identify genes and mechanisms that either promote or block metastatic behavior. Given that the genes we have identified are evolutionarily conserved, the results of such experiments will lend greater insights into the genetic mechanisms that regulate metastasis in humans. Once the genes are identified through genetic work in Drosophila, characterization of them using mouse genetics will immediately follow.


Neurodegeneration & Transcription Regulation

The expansion of polyglutamine tracks has been identified as the cause for a growing number of progressive neurodegenerative diseases including Huntington's disease (HD) and dentatorubral-pallidoluysian atrophy (DRPLA). However, the in vivo functions of Atrophin-1 and Huntingtin, as well as the mechanism of neurodegeneration caused by polyglutamine expansion, is unknown. It has been illustrated by Professor Xu and his students that the Drosophila and human Atrophin homolog functions to repress transcription in Drosophila embryos. To test whether deregulation of transcription dose contribute to the pathogenesis of neurodegeneration in mammal, we have created a transgenic mouse model for DRPLA. Severe neurodegenerative phenotypes develop progressively after the animal reaches its adulthood. Interestingly, this process can be partially suppressed by a compound that involves in transcription regulation. The model could not only help to learn more the role of transcription regulation in neurodegeneration, but also serve as a tool for the development of effective therapies against DRPLA and related diseases.


Mechanisms of Autoimmune Diseases

Lymphocyte development is controlled by a complex array of regulatory molecules including extra-cellular signaling molecules, cell surface receptors, signal transducing kinases, and nuclear transcription factors. Abnormalities in lymphocyte development due to environmental insults or genetic alterations often lead to immune system diseases such as immune deficiency, autoimmune syndromes, or leukemia. We are using the concepts of molecular biology and mouse genetics to investigate the molecular mechanisms lymphocyte development. Professor Zhuang and his student of our institute have recently established a mouse model of Sj鰃ren syndrome, the second most common autoimmune rheumatic disease [Immunity, in press]. This work provides a novel animal model of studying pathogenesis of the disease, the generation of autoimmune cells, and most importantly clues for further clinical prevention, diagnosis and therapy.


Mouse Balancer Chromosome

Although mice share great similarity with human, many useful genetic methods are currently unavailable in mice. One of these is the use of balancer chromosomes. A Balancer chromosome is a particularly useful chromosomal rearrangement that carries multiple inversions, which can effectively suppress homologous recombination within the inverted regions. Originally used in Drosophila melanogaster, balancer chromosomes greatly facilitated the maintenance of recessive lethal mutations, which could play a critical role in large-scale mutagenesis screens in mice. We are currently generating balancer chromosomes of mouse chromosomes 13 and 17. These strains will be extremely helpful for mutagenesis screens that focus on functional annotation of the genes in these two regions, such as the MHC cluster genes on chromosome 17.

Functional Genomics of Model Organisms

Genomics tool has become well established in current biological studies. The sequencing of whole genome has formed the basis for the study of the activity of the whole genome, which is the components of life. Not only when we fully understand how each molecule of life works, but also how they cooperate together, would we be able to know the how life came into being.

This aspect of research at IDM wants to use functional genomics tools (microarray, tissue array, section array, and bioinformatics) combined with other molecular biology tools such as RNAi, etc. to help addressing the questions related to model organism development and mechanism of human diseases.