Hokkaido University Research Profiles


Life Sciences: 45

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  • Life Sciences
  • Information and Communication
  • Nanotechnology / Materials
  • Manufacturing Technology
  • Human and Social Sciences
  • Energy
  • Environment
  • Tourism / Community development
  • Arctic Research
  • Social Infrastructure
  • Open Facilities
  • Equipment for Simultaneous Optimization of Quality and Quantity of Liquid Ice for Freshness Preservation

    Liquid ice optimization system for long-term freshness preservation of food

    We have developed a device that calculates the minimum required amount of food-grade liquid ice (slurry ice (salt water ice) or salt-free water ice) using a simple heat capacity calculation, and that also calculates the salt concentration, water/ice mixing ratio, and shelf life to determine the slurry ice temperature based on the overall heat transfer coefficient (container heat radiation parameter) of the storage container.


    The amount of produced slurry ice, which is useful for maintaining the freshness of marine animals, often exceeded the amount actually used because there was not a calculation method that took storage time into account. At our laboratory, we have developed a device to optimize the quality (salt concentration and water/ice mixing ratio) and quantity (shelf life) of slurry ice simultaneously and quickly on the spot based on the overall heat transfer coefficient of the storage container, as described earlier. Since this method can be applied to the production of fresh water-derived salt-free liquid ice, it can also be used for other food than marine animals (vegetables, fruits, and livestock), and we are currently working to obtain the rights to this invention.

  • MIRASAL, a Device for Visualizing the Freshness of and Best Timing for Eating Food Animals

    A device for evaluating the freshness of and the best timing for eating food animals to ensure safety and security

    In collaboration with the National Institute of Advanced Industrial Science and Technology (AIST), we have developed a visualization device called MIRASAL to evaluate the freshness of and the best timing for eating food animals by using a simulation method to determine the concentration of degraded components in any part of a food animal (aquatic or livestock animal), which changes over the course of time after the animal has died.


    At the wholesale markets in fish and shellfish production and consumption areas, freshness is an important criterion in the determination of transaction prices, and the K value has been proposed as an evaluation index. However, since the K-value is calculated by sampling any part of a postmortem marine animal and analyzing the components after various pretreatments, real-time evaluation (understanding) at the distribution site is not possible. Aiming to solve this problem using an appropriate simulation method, we have developed a device that can evaluate the freshness and the best timing to eat fish and shellfish based on various information such as the type and size of the fish and shellfish, the elapsed time since death, and the storage temperature, using the method described above. We are currently working on the acquisition of the rights to the invention and for improvement of its portability (for use with smartphones, etc.). This device “MIRASAL” can also be applied to livestock animals such as beef, chicken, and pork.

  • Metabolism of Biological Components and Pre-symptomatic Disorder

    Elucidation of the mechanism of non-infectious pathogenesis by considering the metabolism of biological components: Application as a system of evaluating the functionality of foods

    Based on the metabolic analysis of biological components (bile acids, minerals, etc.), we conduct research on the elucidation of the pathogenesis of various diseases and the establishment of pre-symptomatic disorder models using laboratory animals. We aim to elucidate the point of action in prevention of disease onset via dietary intervention.


    The composition of bile acids synthesized by the liver fluctuates with aging and excessive energy intake, and that can be estimated under these conditions. Therefore, by feeding a very small amount of a specific bile acids to experimental animals, it is possible to create a state that mimics the bile acid environment in the corresponding situation. We have found that this results in fatty liver and related pathologies. We also found that a mild deficiency of zinc is a pre-symptomatic disorder model for ulcerative colitis. These findings indicate that minor metabolic changes that occur continuously due to dietary bias (excess or deficiency) are involved in the onset of infectious and non-infectious diseases, and that the experimental system itself, which mimics the situation by controlling dietary components, can serve as a model of pre-symptomatic disorders. Currently, we are constructing various pre-symptomatic disorder models and analyze their pathogenic mechanisms. We are also using these systems to evaluate the functionality of foods.

  • A New Model of Aging by Decreased Protein Metabolism

    Aging causes a variety of metabolic changes. A physical condition of so-called “decreased metabolism” increases the risk of aging, lifestyle-related diseases, and aging-related disorders. We have developed a mouse model that demonstrates aging due to decreased protein metabolism.


    Proteasomes, which are responsible for the degradation of intracellular proteins, are expressed in cells across species and are important for the maintenance of biological functions. Proteasome activity is decreased in older individuals, and the aging-related loss of proteasome function is involved in the development of aging and aging-related diseases. With this study, we created a mouse model in which proteasome activity is decreased and aging occurs. When this model is exposed to a high-fat diet, fatty liver is exacerbated, and when exposed to tobacco smoke, pulmonary diseases occur. By applying this model, we can elucidate the protein abnormalities and target molecules that cause various human diseases.

  • Alpha-defensins Prompting a Paradigm Shift in the Intestinal Environment

    From a scientific understanding of ishoku-dougen (an idea that the same principles underlie a normal diet and medical treatment) to preventive medicine

    The α-defensins secreted by Paneth cells regulate the intestinal microflora and are deeply involved in their elimination and symbiosis. We will evaluate the intestinal environment from the viewpoint that the intestinal environment is defined by the three elements of food, α-defensins and intestinal bacteria, and create a paradigm shift to contribute to the clarification of disease mechanisms and the development of preventive medicine.


    Using isolated small intestinal crypts and enteroids, which are three-dimensional small intestinal epithelial culture systems, we will elucidate the innate immunity of Paneth cells, which are intestinal epithelial cells (that secreteα-defensins), symbiosis with intestinal bacteria, regeneration and differentiation and other molecular mechanisms associated with various functions, taking advantage of state-of-the-art analytical methods such as confocal laser microscopy and flow cytometry. The intestine forms a network between various organs in the body and by analyzing the mechanism of the intestinal environment focused on the function of Paneth cells will make it possible to control the intestinal environment and create preventive measures and treatments for various diseases. From the perspective of the intestines, “food” and “drugs” virtually mean the same thing. We hope to contribute to the realization of a healthy longevity society through industry-academia-community collaboration based on the knowledge we have created.

  • Application of Adhesive Gels to Intraoral Devices

    Innovation for maintaining intraoral devices with adhesive gel

    Intraoral appliances used in dentistry need to be clasped or otherwise attached to the teeth to remain in place. This research involves the development of prototype intraoral floor appliances (e.g., palatal obturator) that are attached to the skin or mucosal side of a polycarbonate frame using PCDME or other types of adhesive gel.


    When an intraoral appliance in this study is used as a palatal obturator, it does not require a clasp, unlike conventional palatal obturators (Fig. 1), because the adhesive gel can be fixed by contact with the oral mucosa. As a result, gingivitis caused by the clasp can be reduced; interference with the sideways growth of the row of teeth can be avoided; it can be comfortably worn without a sense of tightness or pressure; and it is safe to put on and take off the palatal obturator without damaging the oral cavity. It can also be worn before the teeth have erupted, allowing language training to begin at an early stage. The gel can also be thinly spread on the thin frame, and a uniform thickness can be obtained. This reduces the sense of discomfort when wearing the product and ensures a larger oral space, which is effective for language training by expanding the area where the tongue can move.

  • Basic Research to Design Healthy Life Rhythms Considering Biological Clocks

    Japanese people sleep less than the global average, and the economic loss due to sleep disorders is estimated to be about 6 trillion yen per year. At our laboratory we specialize in chronobiology, which is the study of the biological clock, which is deeply related to sleep. Our goal is to contribute to the health of the nation by promoting research of chronobiology.


    The biological clock is an important biological strategy that regulates our behavior (timing of sleep and wakefulness) and our body’s internal environment, so that we can be fully active during the day and get good sleep at night. However, in today's society, many of us are forced to live against our biological clocks due to night shifts, jet lag, 24-hour work schedules, and so on. In order to lead a healthy life throughout our lives, we need to understand the structure and function of our biological clocks, and actively design and optimize our life rhythms according to our life stages and individual lifestyles. At our laboratory, we are studying the mechanism of the effects of light and exercise on the biological clock, the development of effective nutritional dietary guidance methods based on chrono-nutrition, and the relationship between seasonal variations in sleep and biological rhythms and physiological functions.

    Yujiro Yamanaka Associate Professor
    Ph.D. in Medicine
  • Classification of Genetic Information Using Machine Learning

    Predicting the binding of compounds to cell receptors

    Various receptors on the surface of cells play important roles in maintaining homeostasis and environmental responses, but it is difficult to identify compounds that can bind to them. We propose a method for narrowing down the candidates for binding compounds by using machine learning.


    Although the human genome has been deciphered and many of the genes have been elucidated, the structure and function of receptors, which play an important role in homeostasis and environmental responses, have not been fully elucidated, because most of them are membrane proteins and their expression levels are low. Many receptors, however, are expected to be major targets for drug discovery in the future because of their functional aspects, and are thought to be the factors that cause individual differences. We are applying machine learning technology to efficiently narrow down compounds that can bind to receptors.

  • Coherent Raman Scattering Endoscope

    Development of an eye for a novel endoscopic surgical support robot using coherent Raman scattering for label-free nerve visualization

    Raman scattering provides insight into molecular species and structures without staining, but its use has been limited due to its extremely weak scattering. We are developing microscopes and endoscopes that provide Raman images in real-time by using coherent Raman scattering phenomena with ultrafast lasers.


    Raman scattering has been used in chemical analysis, physical chemistry, and semiconductor research because it provides information on molecular species and structures without staining. It is also recently actively applied to the biological and medical fields. However, Raman scattering is very weak. We have developed a multifocal coherent Raman scattering microscope with integrated a wavelength-tunable synchronous picosecond laser and realized imaging at 100 frame/s, which is faster than the video rate. We also demonstrated that nerves are visualized without staining and at high speed under a rigid endoscope of 12 mm in diameter and 550 mm in length. It is expected to be a new imaging tool for nerve-sparing endoscopic surgery.

  • Controlling Plants with Roots

    How to control root regeneration

    Roots are essential organs of many plants, and root injuries heal quickly. This is because a mechanism is at work that maintains the biomass ratio between the roots and the above-ground parts at a constant value. At this laboratory, we have clarified the root regeneration mechanism and have demonstrated the possibility that technology can control the biomass ratio.


    Root pruning (root cutting) has widely been used in horticulture such as bonsai and fruit tree cultivation to empirically control the above-ground parts by controlling the roots. This is a technique that empirically utilizes the fact that the biomass ratio of the roots to the above-ground parts remains constant. We have discovered YUCCA9, a gene that synthesizes auxin, a plant hormone necessary for root regeneration when roots are cut. In the course of our research, we have been able to combine drugs that pharmacologically inhibit root regeneration, and we have also been able to produce plants with genetic traits that prevent root regeneration from occurring.
    Root regeneration is a widespread phenomenon of land plants, and by applying this research to cultivated varieties, it will be possible to increase or decrease the above-ground biomass, which will result in higher yields, labor intensiveness, cost control, and high added value to agricultural and horticultural crop varieties.

    Masaaki Watahiki Associate Professor
  • Development of a Compact Dosimeter Using an Optical Fiber

    Application of ultra-small dosimeters to radiotherapy and diagnostic fields by combining an ultra-small scintillator and an optical fiber

    In recent years, there has been increasing interest in radiation protection against serious skin damage caused by X-ray fluoroscopy. Through this research, we developed a plain ultra-small plastic scintillator dosimeter that does not show up on X-ray fluoroscopic images attached to the end of the optical fiber to prevent late-onset radiation injury.


    For endovascular treatment with X-ray fluoroscopy (IVR; Interventional Radiology), the patient is subjected to prolonged X-ray fluoroscopy. Repeated procedures for myocardial infarction and other conditions may cause ulcers and other serious skin disorders. Conventional dosimeters have the problem that they cause a shadow in the fluoroscopy detection area. In particular, since energy dependence affects the accuracy of measurements, there have been no dosimeters that are compact, have little energy dependence, and do not cause shadows on fluoroscopy. However, the SOF dosimeter developed in this study is characterized by not showing up under X-ray fluoroscopy because the density of the sensor part is close to that of the living body. At present, the SOF dosimeter has achieved sensitivity variation of 5% or less in a range of 60 to 150 kV, and we are working with a company to improve the sensor material to further reduce the sensitivity variation.

  • Development of a Method to Prevent Post-Thoracic Surgery Atrial Fibrillation Using Carnitine

    We will conduct a randomized, multicenter study to determine whether perioperative oral carnitine therapy can reduce postoperative atrial fibrillation (POAF) in patients with valvular heart disease. In case of lung and esophageal cancer patients, a single-arm interventional study will be conducted because similar studies have not been conducted before.


    Postoperative atrial fibrillation (POAF) after thoracic surgery is a frequent problem leading to increased incidences of stroke, heart failure, and infection, and resulting in prolonged hospitalization. Although beta-blockers are the only effective treatment, their efficacy rate is less than 50%, and their side effects often preclude their use. Recently, carnitine preparations, which are fatty acid metabolism ameliorators, have been reported to suppress arrhythmias after myocardial infarction and coronary artery bypass surgery due to their anti-inflammatory and fatty acid metabolism ameliorating effects. As part of this project, we will conduct a randomized, multicenter study to determine whether perioperative carnitine medication can suppress POAF in patients with valvular heart disease. In case of lung cancer and esophageal cancer patients, a single-arm interventional study will be conducted to evaluate the safety and POAF reduction rate, which will be useful for future randomized studies.

  • Development of novel control strategies for intractable diseases in animals

    Development of immunotherapy using antibody drugs and protein preparations for chronic infectious diseases and tumors in domestic and companion animals

    In case of intractable diseases, the elimination mechanisms of pathogens and tumors are disturbed in vivo. This is thought to be due to various immunosuppressive factors that exhaust immune cells. the mechanism of eliminating pathogens and tumors in the body is disturbed, probably due to various immunosuppressive factors that exhaust immune cells. This study is aimed to develop novel formulations that target the immune evasion mechanism and apply them as a novel treatment for animal diseases.


    Research objective: Development of veterinary antibody drugs and protein drugs targeting PD-1 and other immunosuppressive factors and their application to therapeutics. Comparison with and advantage over conventional technology: This approach does not target a specific disease, but rather a wide range of diseases in which the anti-pathogen and anti-tumor effects are lost due to immunosuppressive mechanisms. Since the immunotherapy is based on activated lymphocytes, it is expected to have a multifunctional immune-enhancing effect. Uniqueness of the research: There are limited reports of clinical applications of this approach in the veterinary fields. Characteristics: We will establish therapeutic antibodies for animals and evaluate their effectiveness against various diseases. Efficacy: We aim to provide new treatments for diseases of livestock (cattle, horses, pigs, etc.) and companion animals (dogs, cats, etc.) for which there are no effective vaccines or treatments.

  • Development of Novel Inhibitors Targeting the Receptor-Bound Prorenin System

    Development of drugs that inhibit (pro)renin receptors involved in pathogenesis such as chronic inflammation and angiogenesis

    We are working to elucidate the involvement of the renin-angiotensin system (RAS) in the pathogenesis of diabetic retinopathy and other retinal choroidal diseases, and to develop inhibitors of the (pro)renin receptor, which is upstream of the RAS, and to conduct basic research from a broad perspective.


    Age-related macular degeneration and diabetic retinopathy are retinal and choroidal disorders that major causes of blindness and are regarded as chronic inflammatory disorders associated with lifestyle-related diseases. However, we have yet to develop a fundamental treatment or elucidate the pathogenesis of these disorders. We have previously reported that the receptor-associated prorenin system (RAPS) regulates the molecular pathogenesis of disorders upstream of inflammation and angiogenesis in organ damage in lifestyle-related diseases. We are currently conducting basic research targeting the (pro)renin receptor, which is at the center of the receptor-associated prorenin system, with a view to drug discovery using technologies such as comprehensive small molecule compound screening and drug molecular design methods. Using animal models of diseases, we are also attempting to elucidate the function of (pro)renin receptors and to establish therapeutic strategies for early intervention in disease states while minimizing the impact on the physiological functions.

  • Development of Reagents for Highly Efficient Transfection of siRNA into Immune Cells and Their Application to Cancer Immunotherapy

    Development of next-generation drug delivery systems

    We have developed a reagent (YSK12-MEND) to introduce siRNA into immune cells with high efficiency. If siRNA is introduced into immune cells using this reagent, the expression of immunosuppressive genes can be reduced with high efficiency, and thus it is expected to be applied to cancer immunotherapy using immune functions.


    We have developed YSK12-MEND, a reagent that can efficiently transfect siRNA, a gene expression inhibitor, into mouse and human immune cells. By using the novel reagent, the efficiency of siRNA transfection into mouse dendritic cells has improved more than 10-fold compared to the commercial product (Lipofectamine RNAiMAX). It is known that the function of immune cells is suppressed by cancer cells in cancer patients, although humans have an immune function to fight cancer cells. siRNA delivery using YSK12-MEND can efficiently suppress the expression of immunosuppressive genes in immune cells, which will enable humans to fight cancer cells with their own immune function. YSK12-MEND is expected to be one of the promising candidates for this purpose.

  • Development of Therapeutic Agents and Biomarkers for Stress-induced Diseases

    Molecular psychoneuroimmunology to understand the molecular mechanism of “disease starts in the mind”

    Chronic stress has become a widespread problem in our society as it may lead to sudden death or other serious problems due to overwork or insomnia. We have clarified the molecular mechanism by which chronic stress induces organ damage and sudden death in mice through the activation of specific neural circuits. This system can be used to search for therapeutic targets for stress-induced diseases.


    We are studying the link between stress and disease. Recently, when autoreactive T cells against central nervous system antigens were transferred to mice that had been subjected to chronic stress, the mice suddenly died. The cause of death was heart failure due to hemorrhage in the stomach and duodenum, as found with humans. Stress-specific activation of neural circuits induced microinflammation in the brain, where transferred T cells, etc. were accumulated in specific blood vessels, and a new neural circuit activated by this triggered the gastrointestinal disorder and heart failure. There have been no animal model of stress in which the molecular mechanism has been elucidated, and this model is useful for screening of new drugs for stress-induced diseases. Using this system, we also identified a group of molecules of which the expression is upregulated in specific blood vessels in the brain during stress, and antibodies against these molecules suppressed sudden death. We are also currently identifying marker candidates for autoreactive T cells in humans.

  • Discovery and Application of a Novel Enzyme Capping the N-Terminus of Peptides

    Novel peptide ligase

    ・We discovered a novel enzyme catalyzing the attachment of non-proteinogenic amino acids to the amino termini of various peptides.
    ・It is expected to lead to the protection of useful bioactive peptides and the development of new anti-tuberculosis drugs.


    One of the disadvantages of using peptides as pharmaceuticals is that they are degraded by peptidases. Since exo-type peptidases acting on peptide termini are mostly responsible for degradation in humans, attachments of non-proteinogenic amino acids to the peptide termini is valuable from the viewpoint of protecting them from degrading enzymes for drug development. In this study, as a result of biosynthetic studies of the peptide antibiotic pheganomycin, we found an enzyme that capped the amino terminus of various peptides consisting of 2 to 18 amino acids with a phenylglycine derivative, which is a non-proteinogenic amino acids. To understand the broad substrate specificity, we solved the crystal structure of the enzyme and found that the enzyme has a large substrate binding site, which is not found with other enzymes, and that can thus accept a variety of substrates. Nat. Chem. Biol., 11, 71 (2015).

  • Elucidation and Application of New Functions of Food by Evaluating the Intestinal Environment

    Development of a new intestinal environment evaluation system for food and medicine

    Food materials and ingredients, intestinal bacteria acting as parasites, and host Paneth cell α-defensins are the three elements that determine the “intestinal environment.” We are developing an intestinal environment evaluation system based on the new paradigm that crosstalk between these three elements affects health maintenance and disease to elucidate food functionality and apply it to disease prevention.


    In our original definition of “intestinal environment,” three elements, namely, food materials and ingredients, intestinal bacteria acting as parasites, and host Paneth cells α-defensin, determine the “intestinal environment,” and their crosstalk affects health maintenance and disease. This definition has prompted a paradigm shift in food functionality. The purpose of this study is to clarify the involvement of α-defensins in health maintenance, disease development and pathogenesis. This will help us establish a novel functional evaluation system of food and international criteria to evaluate the intestinal environment. By combining a tissue culture system with an α-defensin quantification system, we will lay the foundation for systematic analysis of the relationship between various intestinal functions and food functions of which the mechanisms are still unknown. This will be the first to elucidate immunostimulation and the control of aging substances by digested food materials and ingredients and drugs. We aim to obtain new scientific indicators to create high added value for food.

  • Elucidation of Nutrient Sensing Mechanisms in the Digestive Tract

    Regulation of blood glucose by food peptides through their effects on the enteroendocrine system

    Hormones secreted by endocrine cells that sense nutrients in the gastrointestinal tract regulate various physiological responses immediately after eating. In the course of studying this mechanism, we found through animal studies that food peptides can promote the secretion of the gastrointestinal hormone GLP-1 and reduce the elevation of plasma glucose levels.


    Various gastrointestinal hormones released by enteroendocrine cells that sense nutrients in the digestive tract, play an important role in regulating various physiological responses after meals. We have focused on the gastrointestinal hormone GLP-1, which is known as an anti-diabetic hormone, and found a food peptide (derived from corn) that strongly promotes the secretion of GLP-1. By orally administering this peptide to rats, we found that GLP-1 secretion was promoted and plasma glucose elevation was suppressed. Our research is aimed to elucidate how this peptide is recognized by enteroendocrine cells, and to control postprandial plasma glucose levels and appetite by controlling the secretion of gastrointestinal hormones with various food components.

  • Establishment of Precision Medicine Targeting Cancer Stem Cells Using Synthetic Polymer Gels

    Development of a method to initialize cancer stem cells using hydrogel

    It is important to eradicate cancer stem cells to cure cancer. This method uses Hokkaido University's original biomaterial (synthetic polymeric hydrogel) to induce reprogramming (initialization) of cancer stem cells rapidly and efficiently, making it possible to predict the properties of cancer stem cells and their response to treatment in case of recurrence.


    It is essential to eradicate treatment-resistant cancer stem cells to cure cancer. However, their number is small, and it is difficult to isolate and analyze cancer stem cells using conventional methods. With this study, we used a synthetic polymeric hydrogel (Science 344, 161-162, 2014) originally developed by Hokkaido University to induce reprogramming (initialization) of cancer stem cells rapidly, easily, inexpensively, and efficiently, allowing us to analyze the properties of cancer stem cells, evaluate their response to treatment, and predict the properties of cancer cells at the time of recurrence. This technology is expected to make it possible to screen drugs that target cancer stem cells, predict the nature of recurrent tumors that may occur in the future, and administer prophylactic drugs, thereby providing cancer patients with accurate cancer stem cell-targeted precision medicine (preventive preemptive medicine).