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Life Sciences: 41
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Health Benefit of Red Algae Phycobiliprotein
Clarifying the health functions and mechanisms of phycoerythrin, which is abundantly contained in red algae dulse
We have discovered that Dulse, an unused red alga distributed along the coast of Hokkaido, is rich in the red protein phycoerythrin (PE), which may have a variety of health functions. Currently, we are analyzing the structure of PE to elucidate the mechanism of its health functions.
Research
Dulse (Palmaria palmata) is a red alga mainly distributed in Hokkaido. It is an unused seaweed that thrives on kelp cultivation ropes during the winter. Dulse prevents the kelp from growing and is thus removed from the ropes. Recently, we have found that Dulse contains approximately 40% protein per dry weight (comparable to soybeans), and its major component is red phycoerythrin (PE), a photosynthetic auxiliary pigment. We have also found that this PE and peptides prepared from PE have health functions, such as ACE inhibition, antioxidation and brain function improvement (Marine Drugs 14:1-10 (2016), Journal of Food Biochemistry, 41: e12301 (2017)).
Hideki Kishimura Professor -
High Strength Gel That Spontaneously Bonds Strongly with Bone Tissue
Development of a safe, high-strength bonding method between wet materials and bone, which has been difficult to achieve so far, by utilizing bone healing in living organisms
In answer to the issue of in vivo fixation by applying the much anticipated high-strength hydrogel as a next-generation artificial cartilage or cartilage tissue regeneration scaffold material, we have developed a simple, non-toxic, high-strength adhesion method using hydroxyapatite, an inorganic component of bone tissue.
Research
The high-strength, high-toughness double-network gel (DN gel) previously developed by our group has excellent properties such as low wear on cartilage and induction of cartilage tissue regeneration in a natural joint, and is being studied for application as an artificial cartilage material and cartilage regeneration induction material. On the other hand, it is difficult to fix and maintain such a gel in a natural joint, which has been a major issue with the practical use of this material. In this study, we developed a fixation method that allows bone tissue regeneration to progress spontaneously into the gel and adhere firmly by compounding hydroxyapatite (HAp), the main inorganic component of bone tissue, to the surface layer of the DN gel. In addition to excellent mechanical properties and cartilage regeneration ability, the realization of non-toxic in vivo adhesion to bone is a great step forward toward the practical application of DN gel for joint treatment.
Takayuki Nonoyama Associate Professor -
Hyperpolarized 13C MRI for Genetic Mutation Imaging
Non-invasive visualization of genetic mutations in tumors by metabolic MRI
The outcome of cancer treatment largely depends on the type of genetic mutation that the cancer cells carry. Using the characteristic metabolic changes brought about by genetic mutations as an indicator, we are developing a molecular imaging technique to identify mutated genes non-invasively using the latest metabolic MRI.
Research
Hyperpolarized 13C nuclear magnetic resonance imaging (MRI) is a state-of-the-art technique for real-time visualization of metabolic reactions in vivo by temporarily amplifying the MRI signal of any compound labeled with 13C tens of thousands of times. It is expected to be a dream molecular imaging technology that can acquire signals from deep inside the body, which is difficult with optical imaging without radiation exposure like PET/CT.
Cells become cancerous through the accumulation of genetic mutations, and the type of mutation greatly influences the response to cancer therapy. Many cancer-causing mutations are associated with characteristic metabolic changes. Hyperpolarized 13C MRI can be used to non-invasively identify mutated genes in tumors by looking at specific metabolic changes.Shingo Matsumoto Professor -
In Vivo Nucleic Acid Delivery System Based on the Development of Unique Functional Lipids
Balancing world-class functional delivery of nucleic acids and safety
We have developed a unique group of functional lipids for the safe and efficient in vivo delivery of siRNA. The lipid nanoparticles containing these lipids showed world-class functional delivery of siRNA in hepatocytes due to their excellent endosomal escape ability and high safety due to their biodegradability.
Research
The key to the practical application of siRNA is the development of superior delivery technology, but there is still much room for improvement in the delivery efficiency. In addition, from the viewpoint of practicality, it is also important to secure a wide safe therapeutic window. It is also highly desirable to develop platform technologies that can provide appropriate formulations for different purposes without being limited to specific applications. To achieve these goals, we have developed a unique group of pH-sensitive cationic lipids. We achieved the modulation of acid dissociation constants, which is an important factor for the pharmacokinetics of lipid nanoparticles, enabling a target-specific molecular design. The lipid nanoparticles containing the novel lipid CL4H6 induced gene silencing in hepatocytes with world-class efficiency. No significant hepatotoxicity was also observed even after the administration of approximately 3,000-fold higher dose for 50% gene silencing, thus a high level of safety was confirmed. CL4H6 was rapidly degraded and eliminated after siRNA delivery.
Yusuke Sato Associate Professor -
Inhibition of Water Freezing by Polyphenols
Toward the application of polyphenol to accelerate supercooling
When some polyphenols coexist with ice-nucleating substances, they suppress ice nucleation activity and consequently maintain the supercooling state. We are trying to elucidate the mechanism of this freezing inhibition effect (supercooling-promoting activity) and to prevent freezing under various conditions.
Research
Silver iodide and ice-nucleating bacteria promote heterogeneous nucleation of water, which in turn promotes freezing of water. Although several compounds that have inhibitory effects on such ice-nucleating activity have been reported, the polyphenol used in this study is a relatively small molecule that can reduce the freezing temperature of aqueous solutions by several degrees by suppressing the activity of coexisting ice-nucleating substances at concentrations as low as several mM. They are also effective to maintain supercooling, even when physical stimuli such as vibration are applied. These polyphenols are also found in various plants, and we are studying conditions for their industrial use. For example, the preservation of plant and animal cells and food in subzero temperatures and the prevention of frost damage to crops are interesting topics. Since the freezing-inhibition effect is affected by various factors, we are examining application possibilities, including the combination use of existing freezing inhibitors, and are trying to elucidate the mechanism of inhibiting ice nucleation activity.
Keita Arakawa Associate Professor -
Liposomal Bioluminescence Immunoassay
Preparation of liposomes encapsulating luciferase and application as an ultra-sensitive label in immunoassays
We have encapsulated the enzyme luciferase (Luc), which catalyzes bioluminescence reactions, in liposome, a lipid bilayer vesicle, and applied it as an ultrasensitive label for immunoassays. As a model substance, we performed immunoassay of C-reactive protein, a marker of inflammation, and found that it could be quantified.
Research
Since immunoassay is an essential technology in clinical laboratories and for environmental analysis, technological advances (simplification, high sensitivity, high throughput, etc.) has come essential as the analytes are becoming more diverse and smaller. We aim to construct an ultra-sensitive immunoassay system in which the bioluminescent enzyme Luc is encapsulated in lipid bilayer membrane vesicles, called liposomes, and use it as a label in immunoassays. By encapsulating a large number of Luc in liposomes, it becomes possible to label antibodies in a stable state. However, although the method of encapsulating enzymes inside liposomes is already known, no studies have been done on Luc. In our study, we have encapsulated heat-stabilized recombinant Luc into liposomes and evaluated the amount and stability of the encapsulation. We have also constructed an immunoassay system for C-reactive protein using Luc-encapsulated liposomes as a label.
Hirofumi Tani Associate Professor -
MALDI Matrix for Sensitive and High-Resolution Structural Analysis of Unmodified Sialylated Glycans and Glycoconjugates
We have developed a matrix that can ionize sialylated glycans and glycoconjugates without modifying the carboxylic acid moiety of the sialic acids, and can analyze them with high sensitivity and resolution (reflector mode) without desorption of the sialic acid residue.
Research
Sialylation (addition of sialic acid) of glycans and glycoconjugates is an important biomarker involved in various biological phenomena such as development, differentiation, disease, infection, and immunity. MALDI (matrix-assisted laser desorption/ionization) is a simple and sensitive soft ionization method. However, the ionization efficiency of unmodified sialic acid-containing glycans is low, and there is a problem that the spectrum becomes complicated due to cleavage of sialic acids or other reasons. With this technique, we succeeded in measuring sialylated glycans and glycoconjugates with high sensitivity and high resolution without undergoing any modification process by improving the addition system to the conventional matrix while suppressing sialic acid desorption. With the change in the cleavage pattern and the increased sensitivity, TOF/TOF analysis and pseudo-MS3 analysis can now be performed using ultra-trace samples. This method does not require chemical modification and separation steps, and enables reaction tracking and rapid sample analysis.
Hiroshi Hinou Professor ProfessorPh.D. -
Micro-/nano-patterns Created with Biomaterials
Bio-based micro-/nano-patterns that mimic biological structures for application to cell culture tools and tissue regeneration
Using biomaterials such as collagen and dental materials, we are producing micro-/nano-patterns that mimic biological structures. Depending on the shape of the pattern and the type of material, it can lead to the improvement of cell functions. While pursuing new possibilities, we aim to apply our technology to cell culture tools and periodontal tissue regeneration.
Research
In this study, we are using nanoimprinting to pattern typical biomaterials. We hope that the designed micro-/nano-scale shapes can be used to control cell functions and contribute to the development of novel cell culture tools and tissue regeneration.
● Comparison with conventional technology: It is characterized by unprecedented production of regular biomaterial patterns, and is expected to contribute to the discovery of new functions. (*Conventionally, irregular, flat or industrial plastics)
● Effectiveness: Patterning greatly improves the number of cells attached and the degree of elongation compared to flat surfaces. It also makes it easy to align cells in grooves. This can lead to the 3D construction of extracellular matrix (ECM).
● Future vision: We aim to regenerate tissues with a similar structure as that of living organisms by developing patterned materials not only in a flat plane but also in 2.5 and 3 dimensions through further layering.Tsukasa Akasaka Associate Professor -
Mitochondria-targeted Nanocapsules (MITO-Porter)
Technology to introduce drugs, proteins and nucleic acids into mitochondria
The mitochondrion is attracting attention as an organelle that contributes to the treatment of diseases, maintenance of beauty and health and the development of the life sciences. We have successfully developed a mitochondria-targeted nanocapsule (MITO-Porter) and are aiming to commercialize this nanocapsule.
Research
The mitochondria-targeted nanocapsules (MITO-Porter) in this study can pass through the cell and mitochondrial membranes to deliver target molecules inside the mitochondria. Conventional technologies using functional elements severely limit the size and type of molecules to be delivered, but the strategy using MITO-Porter, which encapsulates the target molecule, enables mitochondrial delivery independent of the molecular species.
When we prepared MITO-Porter with GFP (green) encapsulated and observed intracellular fluorescence microscopy, we observed many yellow signals that overlap with mitochondria (red), confirming efficient molecular delivery inside the mitochondria. We have also succeeded in introducing genes and nucleic acids into mitochondria, which had been impossible with existing nucleic acid delivery agents (targeting the nucleus and cytoplasm). We are also developing nanocapsules that can be adapted to living organisms.Yuma Yamada Professor -
Modification of Protein Translation Efficiency by Introducing Untranslated Region Sequences
Three-digit increase or decrease in the expression efficiency of recombinant proteins by mimicking viruses
By increasing the efficiency of protein expression per cell to 100 times the current level, we aim to dramatically increase the efficiency of recombinant protein production using CHO cells, etc., realizing a paradigm shift in genetic engineering technology.
Research
Human adenoviruses, which have long been used for gene transfer, are a typical example of a viral vector system with a proven safety profile. Although wild-type adenoviruses have a remarkable ability to shut down host protein expression during infection and express their own late-phase proteins preferentially and explosively, they have not received much attention. Since adenoviruses themselves are pathogenic; however, the use of their viral particles in recombinant protein purification systems is problematic in terms of safety. Therefore, we aim to optimize the leader sequence in the viral gene and incorporate it as an untranslated region sequence upstream of the recombinant protein, so that we can mimic the viral translation system and increase the translation efficiency from existing expression vectors by more than 100-fold. Conversely, it is also possible to modify the untranslated region downstream of the termination codon to reduce the expression level by a factor of several dozens.
Motoaki Yasuda Specially Appointed Associate Professor -
Non-invasive Identification of Cancer Cells by Phase Contrast Measurement
Non-contact optical measurement for high-precision differentiation between cancer and normal cells in culture
The laser beam irradiated at and transmitted through cultured cells attached to the incubator’s bottom generates phase differences depending on the cell’s refractive index and thickness. In this study, we have shown that it is possible to highly accurately differentiate between normal cells and those that have become cancerous in culture by quantifying the phase difference at each point in the cell.
Research
Hoping to contribute to the quality control of cultured cells for transplantation in regenerative medicine, we have sought to establish a non-invasive and highly accurate method to determine the presence of cancerous cells in culture. The special mouse transplantation method, which has conventionally been used to determine the presence or absence of cancerous cells in a cell population, is destructive (invasive) and requires a long time (several weeks or more) to make a judgment. In contrast, this technology can identify cells in culture as quickly as within 10 seconds per field of view, or approximately 10 hours for all cells in a 100 mm dish, by calculating phase difference values that can be quantified non-invasively by simply transmitting laser light through the cells in culture. Since there is no other method to non-invasively determine the presence of cancer cells, which are important to identify for quality control, we are aiming to standardize this method.
Mutsumi Takagi Professor -
Peptide and Glycopeptide Cyclization Technology
Significant improvement of peptide cyclization efficiency by controlling hydrogen bonds
By focusing on forming a hydrogen-bond network in the solvent, we have succeeded in both efficient peptide cyclization and improved solubility of poorly soluble peptides. This system can apply to drug discovery and molecular tool design.
Research
Cyclic peptides are an ideal molecular form for exploring biologically active compounds (drug discovery) and the design of molecular tools in life science. Cyclization of the peptide backbone can control their conformational stability, orientation, and symmetry. However, peptide cyclization requires specific dilution conditions and complex basic protection strategies. We found that combining a hydrogen-bond-controlled solvent system and a base-free condensation agent system enables the efficient cyclization of poorly soluble peptides under highly concentrated conditions. The simplicity of this technology gives a wide range of applications for drug discovery and life sciences by facilitating the free design and mass production of cyclic peptides.
Hiroshi Hinou Professor ProfessorPh.D. -
Reduce Stress on the Liver to Prevent Liver Disease!
To prevent lifestyle-related diseases of the liver (e.g., fatty liver, hepatitis, cirrhosis)
We are analyzing the molecular mechanisms of organ stress, mainly in the liver, for the diagnosis, prevention, and treatment of lifestyle-related diseases. Using our unique optical imaging technology, we are conducting dynamic analysis to explore functional foods and develop new drugs from a new perspective.
Research
In recent years, the number of lifestyle-related diseases such as fatty liver and steatohepatitis has been steadily increasing. These conditions are generally unrecognized and difficult to prevent due to their slow progression and lack of subjective symptoms. However, since these diseases are known to progress to cirrhosis and hepatocellular carcinoma, prevention and suppression of progression are important.
We are studying the molecular mechanisms of the progression of hepatic steatosis, injury, hepatitis, and liver fibrosis caused by various kinds of stress. At the same time, we are searching for functional foods and therapeutic agents to inhibit the progression of disease. Furthermore, we are attempting to conduct unique pathological analysis and construct an in vitro screening system for functional foods and drugs by applying optical imaging technology.Michitaka Ozaki ProfessorMD, PhD -
Rheumatoid AI Diagnostic Research
Simple photographic assessment of joint space narrowing
We will attempt to develop a consulting system that provides objective and detailed quantitative analysis information on destructive joint changes in rheumatoid arthritis patients. The image analysis will be measured based on changes in X-ray images over time using a program we had developed, and the information will be provided to research and clinical institutions in Japan and overseas.
Research
We have been developing and validating software to objectively measure the progression of joint space narrowing on plain x-rays. The latest software, using our original temporal subtraction and contour extraction techniques, is capable of displaying changes (in square millimeters) in the area of the joint space of the target limb.
On the other hand, even from a global perspective, it is difficult to automatically detect the progression of joint space narrowing on plain x-rays using software, and the process still partially relies on manual operation, making it impossible to perform measurement at individual hospitals or clinics. Therefore, the purpose of this study is to establish an internet-based consulting system for quantitative analysis of destructive changes due to rheumatoid arthritis that can meet the needs of domestic and international clients who lead clinical trials and clinical research.Tamotsu Kamishima Professor -
Sonoporation: Development of a New Drug Delivery Method Using Ultrasound and Microbubbles
Realization of tissue targeting capability at the cellular level
We were the first in the world to show that, by irradiating cells with pulsed ultrasound while microbubbles of several microns in diameter are attached to the cells, we can temporarily increase the cell membrane permeability. We are now promoting research aimed at realizing drug and gene delivery to living organisms.
Research
○ Acoustic perforation (sonoporation) using microbubbles and pulsed ultrasound: Pulsed ultrasound irradiation of microbubbles in contact with the cell membrane enables temporary perforation only at the attachment site (Fig. 1). We have realized a method to deliver drugs or genes into any desired position in the target cell by adding drugs or genes to the microbubbles and controlling the attachment site with optical tweezers.
○ Succeeding with therapeutic site identification and drug delivery by using microbubbles and an ultrasound system: A microbubble, which has the target function of adhering only to the cells to be treated, is injected into a vein. To identify the therapeutic site, the tissue where the bubbles have accumulated is detected using an ultrasound contrast method. Pulsed ultrasound waves are then generated to break the bubbles, allowing temporary perforation of the cell membrane and drug delivery (Fig. 2). By adding drugs or genes to the bubbles, highly efficient drug delivery only to the target cells can be realized. -
Susceptibility Testing of Molecular-targeted Therapeutic Drugs
Visualization technique of drug responsiveness in individual cells using fluorescence bioimaging
Fluorescence bioimaging is a technique to visualize the cell behavior at the single cell level. Using this method, we have applied the imaging technology to visualize drug responsiveness and resistance, and to predict future drug responsiveness of patients.
Research
This diagnostic technique uses fluorescent proteins and a fluorescent biosensor based on the principle of F?rster resonance energy transfer (FRET).
By visualizing the drug responsiveness at the single cell level with this biosensor, it has become possible to detect a very small number of drug-resistant cells. As a result, we have achieved a high concordance rate with the clinical course after administration and prediction of future drug responsiveness, both of which were not possible with conventional technology. This technology is not only the world’s first clinical application of fluorescent proteins, but also expected to help assure safety by selecting therapies with guaranteed efficacy. This will also bring economic benefits to medicine by reducing the financial burden on patients and the medical costs. We are now proceeding with this project for chronic myeloid leukemia, which is a blood cancer, as a model. In principle, this technology can be applied to various cancers.Yusuke Ohba Professor -
Technology to Analyze Glycan Patterns Directly from Glycoproteins
The world's first selective ionization technology for glycans that does not require pretreatment
(This is a technology for which Hokkaido University is the sole applicant and sole inventor.)We have discovered the world's first mass spectrometry technique for selective ionization of glycans in complex macromolecules and mixtures such as glycoproteins and body fluids by the MALDI method. We have also demonstrated that this technique can be used for the direct analysis of glycans in complex mixtures such as egg white and body fluids.
Research
Glycan patterns on glycoproteins are important biomarkers because they are factors that determine the disposition of protein in the body. Until now, glycan pattern analysis has required complicated operations such as cutting, chemical modification, and purification of glycans. Mass spectrometry is an ultra-sensitive and high-resolution analytical technique that can directly ionize trace amounts of biomolecules. However, there has not been a method to selectively ionize glycoconjugates such as glycoproteins and glycans in complex macromolecules and mixtures such as body fluids, which requires the complicated pretreatment described above. We have achieved the world's first simultaneous selective cleavage and selective ionization of glycoconjugate glycans, and succeeded in the direct analysis of glycan patterns on glycoproteins. We have also demonstrated that this technique can be used to directly analyze glycan patterns in complex mixtures such as egg white.
Hiroshi Hinou Professor ProfessorPh.D. -
Technology to Create Unique Glycan Derivative Libraries × Microarray Analysis System That Can Be Used Anywhere
Original library using automated glycan synthesis technology × Microarray technology supporting on-site medical care and research
Glycan-related interactions are important targets of infectious diseases and cancer diagnosis. We have developed a microarray system that can be used anywhere to utilize the libraries of glycans, glycoconjugates, glycan-related inhibitors, and their derivatives that have been constructed and accumulated in the process of developing automated glycan synthesis technology.
Research
Microarray technology is a technology that enables simultaneous comparative analysis of the interaction between a large number of compound libraries with well-defined structures and sequences and sample components. We also have the most advanced technology to design and produce our own carbohydrate compound libraries as molecules for microarray analysis based on our automated carbohydrate synthesis technology. The interaction information possessed by carbohydrates is widely used as biomarkers for in vitro diagnostics, such as blood types, serotypes such as O157, and cancer diagnostic markers (CAxx). In addition, we have succeeded in developing an independently powered mobile analyzer that can be used for online diagnosis, such as analysis of infection patterns associated with mutations in infectious diseases and detailed analysis of vaccine effects, by performing specimen collection and microarray analysis on the spot using a smartphone as a terminal.
Hiroshi Hinou Professor ProfessorPh.D. -
Tumor Angiogenesis Inhibitor Screening System
A cell-based screening assay system for the development of tumor angiogenesis inhibitors
We aim to realize cell-based screening using tumor vascular endothelial cells, and contribute to the development of next-generation angiogenesis inhibitor therapies by overcoming problems of existing angiogenesis inhibitors (side effects, lack of companion diagnostics).
Research
Thanks to the development of molecular targeted therapies, antiangiogenic agents are now widely used. However, there are problems such as the lack of companion diagnostics to predict therapeutic effects and side effects due to injury to normal blood vessels.
We have successfully isolated and cultured human tumor vascular endothelial cells and have identified specific markers that they express. Tumor vascular endothelial cells expressing these markers are valuable materials for cell-based screening of novel drugs and compounds, and help us identify new therapeutic targets and drugs that cannot be discovered by studies using conventional tumor cell lines or clinical tumor tissue fragments. Markers expressed by these tumor vascular endothelial cells can also be used as companion diagnostics. This will contribute to the realization of personalized treatment by selecting the target cases as well as the timing and duration of administration with angiogenesis inhibitors.Kyoko Hida Professor -
Understanding the Effects of Monoploidy on Animal Individual Development
Toward the establishment of a single-fold system control technology for industrial use
It is aimed to elucidate the mechanism by which the monoploid state, which has only one set of genomes, causes serious disorders in the development of individual animals, and to establish a technology for creating monoploid individuals that can be used for genetic engineering and strain improvement.
Research
The cells that make up the body of an animal cell are diploid, having two sets of genomes, one maternal and one paternal. In contrast, unfertilized eggs, which normally do not proliferate as such, become monoploid embryos with only the maternal genome, when they are activated to induce individual development (monogenesis). If monoploid individuals can be obtained from them, it will be very useful for genetic engineering and pure line creation. However, in vertebrates in general, monoploid embryos die due to the early developmental abnormality called “hemiparity syndrome,” so the use of monoploid embryo technology has not been realized yet. Using human cultured cells and early mouse embryos as models, we aim to clarify the effects of the monoploid state on developmental processes at the cellular level using molecular cell biology techniques. Based on these results, we aim to establish a cell manipulation method to eliminate the hemiploidy syndrome and to create viable monoploid individuals with stable traits.
Ryota Uehara Associate Professor
