Hidenori Tani's HP  (Japan)
Yokohama University of Pharmacy

Our research

We aim to achieve cutting-edge RNA drug discovery by utilizing molecular biology and bioinformatics.

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◎. The appeal of long noncoding RNA (lncRNA)

  Long noncoding RNA (lncRNA) is a type of RNA. This RNA is generally defined as a transcript of more than 200 nucleotides that does not undergo translation into protein. This means it does not code for genetic information and does not have a function as a protein. In recent years, it has become clear that these lncRNAs play a diverse role within cells, suggesting involvement in important biological processes such as gene expression regulation (HOTAIR), maintaining cellular structures (NEAT1), and disease progression (MALAT1). However, the function of the tens of thousands of estimated lncRNAs is mostly unexplored.
  The charm of lncRNA research lies in the exploration of its unknown diversity and functions. Most genetic information exists as non-coded RNA, and understanding how it is involved in cellular and tissue functions can be said to be a new frontier in biology. It is suggested that lncRNA is involved in many biological processes such as gene expression regulation, chromatin structure maintenance, and cell fate determination. Furthermore, many disease associations have been revealed, suggesting therapeutic potential. Thus, lncRNA research not only provides a new perspective on understanding the essence of life but also has the potential to contribute to medical and pharmaceutical applications.

  In our laboratory, we are focusing on this lncRNA and advancing research, aiming for the elucidation of lncRNA functions and the development of next-generation RNA drugs.

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1. Elucidation of lncRNA functions in humans and mice

　The genomes of humans and mice are approximately 99% identical, and it is known that lncRNAs have many points in common. However, the expression levels and functions of lncRNAs may differ among species, and comparative studies between humans and mice are important for a deeper understanding of lncRNA functions. Furthermore, lncRNAs have been implicated in a variety of diseases. For example, abnormal expression of lncRNAs is observed in many diseases such as cancer, neurodegenerative diseases, and autoimmune diseases. Therefore, it is expected that the study of lncRNAs will be useful for the development of diagnostic and therapeutic methods for diseases. Furthermore, by regulating the function of lncRNAs, we aim to regulate cellular functions and create new therapeutic agents.

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2. LLPS (liquid-liquid phase separation), oxidative stress, and RNA splicing defects

　We will focus on three key words, LLPS (liquid-liquid phase separation), oxidative stress, and RNA splicing abnormalities, and elucidate their relationship to lncRNAs. LLPS (liquid-liquid phase separation) is a phenomenon in which specific molecules aggregate within cells to form droplet-like structures. Recently, lncRNAs have attracted attention for their involvement in the formation of this droplet structure and their important role in regulating cellular functions. Oxidative stress refers to cell damage caused by reactive oxygen species. lncRNAs have been shown to play a protective role for cells by regulating the expression of genes involved in the oxidative stress response. (iii) Abnormal RNA splicing is one of the important causes of abnormal gene expression. lncRNAs have been suggested to interact with proteins involved in RNA splicing and regulate the splicing process. With these three keywords as the axis, we will elucidate how lncRNAs function in the cell and how they affect biological phenomena.

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3. Deep learning-based RNA-protein interaction network analysis

　Deep learning can automatically learn complex patterns that would be missed by the human brain by analyzing huge amounts of data. By applying this technology to lncRNA research, it is expected to clarify the function and mechanism of action of lncRNAs, which have not been elucidated by conventional research methods. Specifically, we aim to discover many previously unknown interactions between lncRNAs and RNA-binding proteins by developing a system that predicts interactions between lncRNAs and RNA-binding proteins using deep learning. lncRNAs have the potential to be an important key to unlocking the mysteries of life. lncRNAs have the potential to be an important key to unraveling the mysteries of life. With the new weapon of deep learning in hand, we aim to lift the veil of mystery from lncRNAs.

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Research Achievements:

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Theme 1: Development of a technique for evaluating the biological effects of chemical substances using human iPS cells
  As mentioned above, animal testing is currently being used to evaluate the biological effects of chemical substances, but the reduction of animal testing has become an international issue due to ethical concerns, and cell testing is being focused on as a solution to this problem. We therefore focused on human iPS cells, which enable evaluation of the effects on each tissue and organ, but require state-of-the-art techniques for culturing and evaluation. Through trial and error, we succeeded in establishing a drug exposure test system using human iPS cells. This achievement enables accurate and rapid evaluation of the safety and toxicity of drugs, and is expected to greatly advance the pharmaceutical industry in the future.

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Theme 2: Discovery of the usefulness of non-coding RNA in cell testing
  As mentioned above, we focused on non-coding RNA (ncRNA), a new biomolecule that has recently attracted attention, and evaluated its usefulness in cell testing. First, we hypothesized that ncRNA might respond more sensitively to drugs than mRNA, and using next-generation sequencers and information technology, we succeeded in demonstrating this hypothesis and disseminating the usefulness of ncRNA as a drug biomarker (ncRNA that responds to drugs with cellular toxicity, etc.). This is a fundamental achievement for future RNA drug discovery utilizing AI (such as RNA vaccines and other RNA-based drugs).

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Theme 3: Development of a method for evaluating the safety of chemical substances using fluorescent RNA probes
  Based on the achievements of Themes 1 and 2, we discovered that RNA degradation is suppressed when chemical substances are exposed to cells. We then devised an idea for evaluating the safety of drugs based on RNA degradation and succeeded in developing a novel technology for rapidly and sensitively evaluating the safety of drugs by designing fluorescent RNA probes that respond to degradation. This new technology allows for identification within 2 hours, compared to the conventional method, which required at least 24 hours. This achievement is a considerable advantage in drug development.

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Themes other than the ones mentioned above:

  Clarification of GAS5 (lncRNA) function
→ Focusing on the degradation rate of GAS5 RNA to elucidate its function.

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  Development of BRIC-Seq method
→ Successfully developed a method to measure the degradation rate (half-life) of all RNAs in human cells

genome-wide.

→ Discovered that lncRNAs with a short half-life (less than 4 hours) have a high possibility of being functional RNAs.

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  Exploration of HCV RNA helicase inhibitors
→ Discovered numerous potential HCV treatment drugs focusing on HCV's RNA helicase activity.

  Development of universal Qprobe method
→ With only one type of QProbe (fluorescence quenching probe), it is possible to perform real-time PCR for multiple genes.

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  Development of ABC-PCR, ABC-LAMP method
→ Even when a sample contains a large amount of PCR & LAMP inhibitors, it is still possible to accurately measure the amount of genes.