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- Laboratory of Basic Biology
The research purpose of our basic biology laboratory is to elucidate the elementary processes of vital reactions by making full use of techniques based on molecular biology, biochemistry (enzymology), and cell biology. We promote original drug discovery research based on the results obtained in our studies. Furthermore, we provide technical support for the drug discovery research of IMC by developing experimental systems that can verify the mode of action of novel compounds. We have particularly elucidated the elementary processes underlying the systems of gene expression in eukaryotes using various systems, including RNA viruses.
- Protein synthesis and translational control.
- a) Research on translation regulatory networks used by RNA-binding proteins.
- b) Establishment of implantable biosensor technology innovations using nucleic acids.
- c) Establishment of experimental systems for mode of action analysis.
- Poliovirus
- Influenza virus
1. Protein synthesis and translational control.
Expression of the genetic information transcribed from DNA into mRNA is controlled by complicated and sophisticated regulatory systems that include regulatory sequences in mRNAs, miRNAs, and various RNA-binding proteins; this expression determines higher order vital cellular phenomena. Because of various RNA-binding motifs, RNA-binding proteins bind to a specific mRNA in a specific manner. Of these post-transcriptional gene expression regulations, mRNA transport to appropriate sites and local translational regulation provides an optimal mechanism for controlling gene expression in a spatiotemporal manner. Until date, we have examined whether or not HuD, a neural-specific RNA binding protein, can actually regulate translation using an original in vitro translation system with cell extracts that can reconstitute the translation from cap-poly(A) mRNAs. In this assay system, we can strictly quantify cap-dependent translation. Using this system, we will elucidate how the linkage system of translational regulation by neuronal Hu proteins and signaling pathways plays a role in neuronal differentiation. On the other hand, miRNAs are potent regulators of gene expression that repress translation and accelerate degradation of target mRNA. Recently, evidence regarding the close correlation of Hu proteins with miRNA machinery was obtained. On the basis of these findings, we hypothesized that these two factors act antagonistically and cooperatively. We aim to prove this hypothesis by making full use of techniques based on molecular biology, biochemistry, and cell biology. The results derived from this research will reveal the regulatory networks of translation that are modulated by neuronal Hu proteins during neuronal differentiation. Our final research purpose is to elucidate the mode of action by which neural cells acquire polarity based on the finding that Hu protein-mRNPs (mRNA-protein complexes) play a role in the activation of mRNA-specific translation mechanisms. Moreover, we attempt to establish implantable biosensor technology innovations using nucleic acids.
2. Poliovirus
Our aim is to gain an insight into the molecular mechanisms of the replication and pathogenicity of poliovirus, a neurotropic virus. In humans, poliovirus infection begins with oral ingestion of the virus. The virus multiplies in the alimentary tract and then enters the circulation. The circulating virus then invades the central nervous system through the blood brain barrier and replicates mainly in motor neurons. Paralytic poliomyelitis occurs as a result of the destruction of neurons induced by the lytic replication of the virus. In addition to the main dissemination pathway a neural pathway is known to exist. We are particularly interested in elucidating the molecular mechanisms of the two dissemination pathways of poliovirus.
3. Influenza virus
Influenza virus binds to sialic acid on the cell surface (1) and is incorporated into the cell by endocytosis (2). Influenza virus genome RNA is released into the cytoplasm (3) and transported to the cell nucleus. In the nucleus, the viral genome is transcribed to produce viral mRNAs; it is also replicated to produce progeny genome RNAs (4). After transcription and replication, viral mRNAs as well as progeny genome RNAs are transported to the cytoplasm. The viral mRNAs are translated to synthesize viral proteins. Viral proteins and progeny genome RNAs are assembled at the plasma membrane (5), and progeny virions are released from the cell surface (6). Amantadine inhibits membrane fusion during viral genome RNA release into the cytoplasm, and Tamiflu and Relenza inhibit release of progeny virions from the cell surface. However, it is necessary to develop new anti-influenza drugs because viruses resistant to these drugs have been isolated. Thus, we now analyze the molecular mechanisms of transcription and replication of the influenza virus genome as well as the assembly of viral particles and attempt to develop new anti-influenza agents (drugs) based on our findings.
