Development of a laser thrombolytic system

Currently, the thrombolytic agent rt-PA is used for treating acute cerebral infarction in the world. However, the risks of cerebral bleeding and other side effects result in the limited application. In addition, endovascular interventions (e.g., Trevo Pro, REVIVE SE) are also applied to treating acute cerebral infarction. Yet, those devices are not completely free from clinical problems, e.g., risk of vessel injury, indicating the need for safer, quicker, and more reliable recanalization approaches. We have therefore developed a new thrombolytic method by taking advantage of light energy. A physician-led clinical trial has been started since 1st December 2016. The goal is the clinical development of a highly effective laser thrombolytic system with low incidences of bleeding complications and other side effects, thereby providing competitive advantages.

Functional analysis on coagulation / fibrinolytic factors in a mouse model of type IIa familial hypercholesterolemia.

A murine genetic model of LDL-cholesterol (LDL-C)-driven atherosclerosis, based on complete deficiencies of both the LDL-receptor (Ldlr^-/-) and of a key catalytic component of an apolipoprotein B-edisome complex (Apobec1^-/-), that converts apoB-100 to apoB-48, has been extensively characterized. These gene deficiencies allow high levels of apoB-100 to be present and inefficiently cleared, thus leading to very high levels of LDL-C in mice on a normal diet. Many key features of atherosclerotic plaques observed in human familial hypercholesterolemia are found in these mice as they are allowed to age through 72 weeks. The general characteristics include the presence of high levels of LDL-C in plasma and macrophage-related fatty streak formation in the aortic tree, that progressively worsens with age. More specifically, plaque found in the aortic sinuses contains a lipid core with relatively high numbers of macrophages, and a smooth muscle cell α-actin- and collagen-containing cap, which thins with age. These critical features of plaque progression suggest that the Ldlr^-/-/ Apobec1^-/- mouse line presents a superior model of LDL-C-driven atherosclerosis.
We are using this model mouse to investigate coagulation / fibrinolytic factors by introducing the corresponding genetic modification using CRISPR / CAS9 in vivo.

Elucidation of the mechanism of exacerbation of cerebral hemorrhage caused by oral bacteria

Previous studies have shown that oral bacteria, S. mutans, may be one of the risk factors for intracranial hemorrhage. Our study has shown that highly pathogenic bacteria among caries-causing bacteria accumulate at the site of cerebrovascular endothelial injury, enhance production and activity of matrix metalloproteinase (MMP)-9. The MMP-9 melt the extracellular matrix of blood vessels, which has shown the possibility of exacerbating intracranial hemorrhage. Moreover, we have found that collagen-binding protein (CBP) was expressed on the surface of bacteria. We are now researching on the mechanism of production and activity of MMP-9 by CBP.

Clinical pharmacological research in translational research (TR) facility

We have established a facility at a national university to conduct clinical trials for healthy subjects in Japan for the first time. We conduct industry- or investigator-initiated clinical trials and promote drug discovery. The TR facility attached to the Hamamatsu University hospital has 12 beds and specializes in clinical research. In recent years, a phase I physician-led trial (First in Human study) for healthy subjects with new drugs from academia has been conducted.