Research Center for Water Biology and Medical Sciences

We advocate for the novel concept of "Water Biology" and aim to comprehensively understand life phenomena from the perspective of water molecule dynamics. By integrating cutting-edge knowledge and technology from physical chemistry, biology, and medical sciences under the common theme of "water," this center aims to deepen the physicochemical understanding of water molecule dynamics in living organisms and apply this knowledge to biology and medicine.

Water molecules, aquaporin, MRI, multiphoton microscopy, near-infrared spectroscopy, molecular dynamics simulation

■ Activities Continuing from FY2019: Background, Rationale, and Goals

Water-Viewing Project:

We will observe guinea pig pancreatic duct double perfusion using a CARS microscope and, continuing from the previous fiscal year, attempt to quantitatively analyze transcellular and paracellular water movement. The goal is to quantify transepithelial water movement and construct a model. We will also advance the observation of water dynamics within the brain parenchyma using acute mouse brain slices and examine changes under osmotic stress.

Water-Understanding Project:

We aim for an integrated understanding of in vivo water dynamics using a simulation model. We will attempt to improve the accuracy and practical application of the model completed last fiscal year. Specifically, we will predict fluctuations during water or salt loading. We will also proceed with studies in an open system, with a particular focus on thoroughly examining the relationship with osmotic pressure.

Water-Controlling Project:

(1) We aim to elucidate the regulatory mechanisms of AQP4 and the physiology and pathology of cerebral lymphatic flow. Specifically:

1) To capture changes in the expression and localization of AQP4 due to development and aging in mice.

2) To observe changes in diffusion and convection in the brain parenchyma using AQP4-deficient mice.

3) To elucidate the role of AQP4 in the pathology of Alzheimer's disease by crossbreeding AQP4-deficient mice with Alzheimer's models. We will analyze multiple types of Alzheimer's model mice, not just one.

■ New Activity Goals, Content, and Implementation Background for FY2020

Water-Understanding Project:

We will develop a mathematical model to predict relative blood glucose levels from the "sugar-water dynamics" of subcutaneous interstitial fluid.

Water-Controlling Project:

We aim to elucidate the changes in the regulatory mechanisms of AQP2 associated with aging and their underlying mechanisms. Specifically:

1) To examine changes in the expression, localization, and vasopressin reactivity of AQP2 due to development and aging in mice, using models such as water restriction. 2) To examine the effects of chronic water loading on the expression and localization of AQP2. AQP2 is the most important aquaporin for body water balance in mammals.

This time, we will analyze these changes along the temporal axes of the life cycle and circadian rhythm.

■ Implementation Details, Research Outcomes, and Degree of Achievement Relative to the Fiscal Year Business Plan

Water-Viewing Project:

We attempted to quantitatively analyze transcellular and paracellular water movement by observing guinea pig pancreatic duct double perfusion with a CARS microscope. Through trial and error, we became able to perform pancreatic duct double perfusion almost without issue. Furthermore, we succeeded in obtaining CARS signals from the water within the lumen. This fiscal year, we advanced the data analysis and solidified the foundation for constructing a model of epithelial water permeability.

Water-Understanding Project:

(1) Analysis of the correlation between female hormone fluctuations during the menstrual cycle and near-infrared light spectra of the skin for ovulation prediction: By increasing the number of subjects and advancing verification, we were able to classify the three days before and after ovulation from other days with nearly 100% accuracy.

(2) Integrated understanding of in vivo water dynamics using a simulation model: We introduced i) pulsatile flow into the cardiac output system (WBW6) and ii) multi-segmentation of the aorta and vena cava (WBW7) to the Whole Body Water dynamics simulation program ver. 5 (WBW5), which was completed at the end of the last fiscal year. As a result, for aortic pressure, we successfully reproduced the delay of the peak systolic pressure along the segments and the decrease in pulse pressure. For vena cava pressure, we succeeded in reproducing a mild negative pressure with minute pulse pressure. We are also attempting dynamic analysis in an open system that considers water influx and efflux. In the future, we plan to develop this into a model that incorporates osmotic pressure.

Water-Controlling Project:

AQP4 is an aquaporin expressed in the mammalian brain, and its connection to the mechanism of cerebral lymphatic clearance has recently garnered particular attention. Furthermore, its role in the pathophysiology of Alzheimer's disease is becoming clearer. Therefore, in this project, we will investigate the molecular regulatory mechanisms of AQP4. We will also clarify the relationship between AQP4 and Alzheimer's disease using transgenic mouse models. It was confirmed that behavioral abnormalities become prominent with aging in AQP-deficient mice. We intend to thoroughly elucidate this mechanism in the future.

Number of major publications: 5

Major journals: Proc. Natl. Acad. Sci. USA, J. Phys. Chem. A., Mol Neurobiol, J Neurochem, B: Biointerfaces

Number of conference presentations (domestic and international): 13

Visualization of water dynamics in the brain parenchyma has become possible. We developed model mice to investigate the relationship between AQP4 and Alzheimer's disease and discovered that they exhibit a prominent phenotype.