Research Group
Aquaporin water biology｜Non-liniear optics, neuroscience｜Tissue engineering
Computer simulation｜Research Support Team
Our research staff members, who have various backgrounds, create their own teams at the department. They maintain their creativities and communicate with each other, therefore very flexibly and dynamic research environment has been established in our department. While making the best of each team’s study, we are continuing to progress our researches in order to reach our goal - contributing to the medicine that is based on the deeper comprehension of the life phenomena.
Aquaporin water biology
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chief | Masato Yasui |
| member | Yoshinori Yukutake、Shoji Tsuji、 Kimiko Tatsumi、Ikuko Sugiura、 Go Yoshida、Yoichiro Abe |
Water constitutes roughly 70% of the mass of our body. Water metabolism is one of the most important homeostatic function. There is a dynamic and precise regulation for water balance in our body; secretion such as tears or saliva and absorption in digestive tracts or kidney. Disturbance in water balance can be seen in many clinical disorders from dry syndromes to brain edema. Behaviors of water molecules in our body have not been well understood although it is involved in many aspects of pathophysiology. However, discovery of water channel, aquaporin led us understand water metabolism, secretion and absorption at a molecular level.
To establish “Water Biology”
In many cases, scientists have tried to understand life phenomenon without thinking of the importance of water molecules since it is too natural that water molecules exist everywhere. We try to understand life science based on the behaviors of water molecules in nano-environments by focusing on water molecule itself. How do water molecules contribute to the complex of life phenomenon, especially self-organization under non-linear open system? To address these questions, we apply computer simulation and non-linear optics in order to visualize the behaviors of water molecules in nano-environments.
Ongoing projects:
1.Aquapoins in brain
AQP4 is a predominant aquapoin in mammalian brain. AQP4 plays a role for brain edema formation associated with brain tumors, cerebral vascular diseases, etc. However, physiological relevance of AQP4 is mostly unknown. Recently, it has been shown that AQP4 may be involved in mood disorders such as bipolar disease and auto-immune demyelinating disease, NMO (neuromyelitis optica). We suspect that AQP4 might be related with mechanisms for general anesthesia. We focus on AQP4 function to understand higher brain functions, and to target for drug development against mood disorders, seizures, and brain edema.
2.Structure and function of aquaporins
Atomic structural models of aquaporins have made us possible to understand how water molecules pass through the aqueous pore of aqaporins. We apply molecular dynamics simulations and quantum chemical calculations to analyze permeability and conductance of aquaporins as well as to use molecular biological and biochemical methods.
Non-linier optics, neuroscience,
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chief | Mutsuo Nuriya |
| member | Hideki Miwa、Yuri Kamase |
1.Background
Understanding the mechanism of our higher brain functions remains to be a big challenge in both basic and clinical medicines. Human brain is considered to possess ~1011 neurons and these individual neurons constitute a fundamental unit of the brain functions. Therefore, understanding the computational functions of individual neuron is essential to the pursuit of brain functions. However, a large part of such neurons’ computation remains unclear. One of the biggest reasons for this is the lack of an appropriate method that allows investigations of electrical properties in small structure such as synapses, and critical location in information processing in neurons. To overcome this hurdle and to unveil the mysteries of neuronal information processing, our group is applying a novel optical technique together with conventional methods to neurons.
2.Technique
Toward the understanding of electrical properties of dendrites, we are applying a wide variety of methods including a novel optical method, electrophysiology and biochemistry.
Application of two-photon microscopy, a form of nonlinear optics, to neuroscience has dramatically advanced our understanding in neuronal physiology. Second Harmonic Generation (SHG) is also an example of such nonlinear optical phenomena, but it has a unique property of its requirement for an asymmetric environment such as membrane interfaces. Therefore, SHG signals come only from plasma membrane when a dye is applied to neurons (Fig 1&2). Utilization of membrane potential sensitive dyes as an SHG media makes it possible to use SHG to probe local membrane potential changes in cells. Due to its membrane selectivity, such SHG-based membrane potential imaging provides quantitative information of membrane potential in addition to qualitative one that could be obtained from other imaging techniques (Fig 3). This unique property of SHG makes it the only available quantitative potential imaging technique among other imaging methods. Employing this novel technique, our group is performing physiological and pharmacological experiments at fine, albeit critical structures that had been beyond the reach of conventional pipette-based electrophysiological recordings.
Further applications of physiological understandings provided by such technique require more detailed knowledge at molecular and cellular levels. Therefore, we are employing other molecular and cellular techniques in addition to the imaging techniques mentioned above.
3.Projects
■ Membrane potential recording in dendrites by SHG
Membrane potential dynamics in dendrites and spines upon neuronal activity remains largely unknown. Therefore, our group is applying SHG together with electrophysiological recordings to investigate the nature of membrane potential changes in these structures upon physiological stimulations.
■ Dynamics of voltage gated ion channels in dendrites
Processing of membrane potential information in dendrites is supported by various types of voltage gated ion channels. The dynamics of these channels are considered to regulate the nature of neuronal information processing both in normal and pathophysiological conditions. Therefore, our group is studying the dynamics of these channels mainly using biochemical approaches.
Tissue engineering
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chief | Ken Kobayashi |
| member | Takeshi Arimitsu、Hiroyuki Yamamoto |
1.Self-assembly of cells
Human body is consisted of more than 100 kinds of about 60 trillion cells. Although these cells have distinct abilities respectively, a solitary cell hardly exercises the abilities. The cells establish a complicated and artful organization through the reciprocal cell-cell interactions and the interactions with extracellular matrix, endogeneous and exogeneous soluble factors, which are produced by them. The phenomena that the cells constitute the functional tissues are referred to as self-organization. The various patterns of self-organization are observed in various tissues during developmental processes.
2.Reconstructed tissues
The self-assembly can be also observed in the in vitro cell cultures. The cultured epithelial cells don’t functions as the epithelium when the cells exist alone. However, when the cells form closely linked sheet-like structure by the optimal culture conditions, they become to reveal the various epithelial functions such as material selective penetration through the transporter and the channel molecule, the barrier function by tight junction, and mucociliary function with the cilia and mucus. The functional cell aggregation developed from the undifferentiated single cell is referred as the reconstructed tissue. The reconstracted tissues can be utilized as the in vivo tissues of lab animals or human and contribute to the biological, medical and pharmacological science.
3.Ongoing research projects
■Amniotic fluid regulatory mechanism
Amnion is the organization that envelopes the developing embryo with the amniotic fluid. The embryo absorbs necessary elements for the development from not only funiculus umbilicalis but also the amniotic fluids. However, the amniotic fluid regulatory mechanism by amniotic membrane remains unknown. We have succeeded to form the functional reconstituted amniotic membrane made from human amniotic epithelial cells and fibroblasts. This model can be used for the mass transfer experiments.
■Blood brain barrier
Blood-brain barrier is a membranic structure that acts primarily to protect the brain from chemicals in the blood, while still allowing essential metabolic function. It is composed of endothelial cells, astrocyte, and pericyte, which are packed very tightly in brain capillaries. Overcoming the difficulty of delivering therapeutic agents to specific regions of the brain presents a major challenge to treatment most of the brain disorders. We investigate the regulatory mechanism of the tight junctions of blood brain barrier by using various types of the reconstituted blood brain barrier models.
Computer simulation,
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chief | Yoshinori Hirano |
| member | Shin Suzuki、 Hiroyuki Simizu、Tetsu Narumi、Kenji Yasuoka |
1.Background
Our life is maintained based on the function of bio-molecules, including proteins. The advanced techniques and equipments in biochemical experiments have led us understand how bio-molecules function. It becomes more important to analyze the structural dynamics of bio-molecules and their interactions at both atomic and molecular levels. However, it is difficult to obtain information regarding to the interactions only by the biochemical experiments. We therefore introduce computer simulations such as a molecular dynamic (MD) simulation or a quantum chemical calculation to understand complex life phenomenon. We can obtain the dynamic information of the molecules and the atoms at a high resolution by MD simulation. We hope that theoretical methods lead to the better understanding of life phenomenon. In addition, we will perform an in silico docking study to predict the interaction between ligands and the target proteins.
2.Methods
The structures of proteins have been clarified little by little by the crystal analysis such as X-ray and NMR methods, at a molecular and an atomic level. The structures of proteins that have been determined are provided in Protein Data Bank (http://www.pdb.org/pdb/home/home.do). In addition to a crystal or static structure, dynamic information is necessary to clarify functions of the protein. Molecular dynamics (MD) simulation is a method of understanding structural dynamics of the protein at a molecular and an atomic level. It is expected that we can obtain the information of structural dynamics of the bio-molecule at an atomic level, because it is difficult to obtain that only by biochemical experiments. We expect to analyze catalytic mechanisms of the protein at both an atomic and an electronic level by using quantum chemical calculations.
3.Ongoing projects
We are studying the molecular mechanisms of bio-molecules, for example aquaporin (AQP), using theoretical methods.
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Clarification of permeation and regulation of AQP using MD simulation.
We focus on the regulation of AQP permeability. We also study if AQP is permeated by gasses such as CO2 and NO by MD simulation.
- Clarification of the proton exclusion mechanism of AQP using quantum chemical calculations. The model of the quantum chemical calculation is constructed from the result of MD simulation, and the proton exclusion mechanism of AQP is being studied at an electronic level.
Research Support Team
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chief | Hao-Yang |
| member | Mitsuko Shiota、Manae Imamura、Yuri Kamase |
It is necessary for the research team to have the various aspects of supports in order to manage the entire research teams smoothly. We want to collaborate with these research teams to make their communication work efficiently as well as to support their managements such as obtaining the research funds, maintaining their facilities, and planning the social activities. We believe that our goal is to assist the researchers in many ways so that they can focus on their studies and show their results of the studies to the society. We will help their classes and practices of the department going smoothly.