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Life Sciences: 43
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- Information and Communication
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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.
Research
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.
Naoto Tsubouchi Associate Professor -
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.
Research
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.
Naoto Tsubouchi Associate Professor -
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.
Research
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.
Satoshi Ishizuka Professor -
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.
Research
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.
Utano Tomaru Associate Professor -
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.
Research
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.
Tokiyoshi Ayabe Emeritus Professor -
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.
Research
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.
Tomoo Kaneko Lecturer -
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.
Research
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 ProfessorPh.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.
Research
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.
Toshinori Endo Professor -
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.
Research
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.
Mamoru Hashimoto Professor -
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.
Research
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.
Research
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.
Masayori Ishikawa Professor -
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.
Research
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.
Yasushige Shingu Lecturer -
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
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.
Satoru Konnai Professor -
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.
Research
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.
Susumu Ishida Professor -
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.
Research
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.
Takashi Nakamura Assistant Professor -
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.
Research
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.
Masaaki Murakami Professor -
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.Research
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).
Tohru Dairi Professor -
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.
Research
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.
Kiminori Nakamura Associate Professor -
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.
Research
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.
Tohru Hira Associate Professor -
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.
Research
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).
Shinya Tanaka Professor -
Flexible and Strong Gel
New materials for the age of welfare
What kind of material should be used in an age when we are required to improve our quality of life? The answer is strong gels such as double network gels. Tough gels will help revolutionize the quality of medical devices, tissue substitutes and biomimetics.
Research
Conventionally, elastomers have widely been used as soft materials, but in situations where they are used as contact points with living organisms or as their substitutes, hydrophobicity is a critically important factor. Since hydrous materials strongly reflect the physical properties of water, they exhibit physical properties that are very similar to biological tissues. For example, heat transfer and electromagnetic wave absorption properties of hydrous materials are similar to those of living tissues, and their surface friction is as low as that of body tissues. Although gel is the most common hydrophilic soft material, its mechanical strength has been low and its application has thus been limited. We have succeeded in developing a highly strong double network (DN) gel that does not break, even when a truck drives over it, despite 90% water content. This has greatly expanded the possibilities of gel applications. While working to examine the toughness of DN gels, we have discovered the “sacrificial bonding principle,” arriving at the concept of strengthening various materials. In recent years, we have been developing various other types of strong gels besides DN gels.
Jian Ping Gong Professor -
Functional Modification of Food Proteins
Sugar modification for processing and improved health functions
Using the Maillard reaction to bind sugars to fish meat proteins, we can prepare water-soluble muscle proteins and peptides with modified processing properties and health functions (anti-inflammatory and antioxidant function, suppression of blood pressure increase and suppression of lipid absorption, etc.). It can also be applied to livestock and poultry meat and various proteins.
Research
Summary
The Maillard reaction can be used to bind reducing sugars to proteins and peptides to create new fish food products with modified properties.
Comparison with conventional technology and uniqueness
High-molecular complex proteins such as muscle proteins are prone to thermal aggregation, and progression of the Maillard reaction leads to deterioration of various properties. We have developed a new method to create functional materials from unstable proteins such as fish food proteins by controlling both protein denaturation and the Maillard reaction.
Characteristics of the materials and manufacturing technologies that can be created.
1. Introduction of sugar chains without using chemical reagents
2. Making muscle soluble in water and adding highly emulsifiable properties
3. Improving the stability of unstable proteins
4. Modification of in vivo active health functions
5. Can be applied to the development of functional peptides.
6. No limitations on the form of the raw materialsHiroki Saeki Professor -
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 Associate 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 Assistant 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 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.Nobuki Kudo Associate Professor -
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 -
Understanding the Mechanism of Fish Egg Formation and Applying Research
Improvement of aquaculture technology, development of ecological and environmental research technology
The growth of fish larvae mainly depends on the substances accumulated in the eggs. Therefore, the synthesis and accumulation of egg constituents are important processes that affect egg quality. We are studying the details of this process and its control mechanism (egg formation system). We are also conducting applied research using this system.
Research
Fish eggs grow rapidly while storing various substances such as proteins, lipids, sugars, vitamins and hormones as yolk in their cells. These yolk substances are important nutrient sources that affect the quality of the hatchlings. In addition, the growth of eggs is a process in which various biological molecules, including genes, proteins and hormones, closely work together. This process varies by fish species and environmental factors such as light and water temperature affect the profile of these internal factors and regulate the egg growth. We are conducting detailed comparative analysis of the egg formation process in a wide variety of fish using life science techniques (immunobiochemistry, molecular biology, cell biology, etc.). Based on this basic research, we are also conducting applied research such as the monitoring of environmental hormone pollution, the development of a fish egg species identification method and the development of a simple fish sex identification method.
Naoshi Hiramatsu Associate Professor
