高橋 賢

Scientific achievements and potential impact on the global challenges

Scientific achievements and potential impact on the global challenges

Research - Ken Takahashi

SCIENTIFIC ACHIEVEMENTS 2010-2021

I discovered a new molecular target associated with the development of myocardial infarction. This research is currently ongoing and its results may help to prevent stroke and organ damage after organ transplantation. I have obtained one patent in connection with this research, published nine academic papers and issued four press releases, including one at EurekAlert! To further develop this line of research, I built an organ-on-a-chip as a visiting scholar at the Harvard University. These studies were supported by three grants from the Japan Society for the Promotion of Science. 

I promoted scientific research through international collaborations. I am currently collaborating with a Thai researcher through a joint research project with the United Nations Conference on Trade and Development (UNCTAD) and our institution. In addition, I hosted a researcher from Myanmar within the frames of a collaborative research programme with the Ministry of Health and Sports of Myanmar. Furthermore, I took part in activities aimed at international human development and nurture of future science leaders by strengthening the co-operation between four universities in the People’s Republic of China and our institute.  

関連記事: UNCTADによる研究者育成プログラムの初会合

I have provided my expert opinion and reviewed 83 manuscripts for high-impact international journals, maintaining the integrity of scientific communication and supporting unbiased and fair peer review practices. More than 20 of these manuscripts have been published, significantly contributing to fundamental and applied scientific knowledge. I am also an Editorial Board member of five international scientific journals. 

Discovery of a new molecular target related to the development of myocardial infarction: Aiming to achieve a society where people can live in good health for a long time 

My team discovered a new target molecule, the TRPM4 channel, associated with the development of myocardial infarction in experiments on excised rat hearts (PLoS ONE 2013; 8 (7): e70587). In addition, in an experimental system in which the TRPM4 gene was knocked out by CRISPR/Cas9, we revealed that cardiomyocyte death, which causes myocardial infarction, is a response to oxidative stress mediated by the TRPM4 channels (Biochem Biophys Res Commun 2021; accepted). Furthermore, in order to study the effect of this mechanism on the development of human myocardial infarction, we developed a model of ischemic heart disease using cardiomyocytes differentiated from human iPS cells (J Vis Exp 2020; 159: e61104). 

To further develop these findings, I performed experiments with an organ-on-a-chip for one year and four months as a visiting scholar at the Wyss Institute for Biologically Inspired Engineering at the Harvard University. This study was supported by three grants from the Japan Society for the Promotion of Science. This research resulted in one granted patent (Japan Patent No. 6073125) and one patent application (Japan Patent Application No. 2020-084982). Nine academic papers were published in international academic journals, and the results were communicated in press releases via international news sites such as EurekAlert! (4 releases). 

Furthermore, my research team is elucidating the mechanism by which TRPM4 channel activity damages organs other than the heart due to ischemia-reperfusion. Further development of this line of research may lead to the prevention of stroke and organ damage after organ transplantation. 

Promotion of scientific research through international joint projects – international co-operation through science 

With the rise of nationalism hindering international co-operation, I have promoted scientific research through international joint projects with the belief that international co-operation through science will lead to the development of a peaceful world. 

For example, I am conducting joint research with a young Thai researcher through a human resources development programme implemented under a comprehensive co-operation agreement between the United Nations Conference on Trade and Development (UNCTAD) and my institution, the Okayama University. In addition, I am taking part in the international exchange through science by hosting a Myanmar researcher via a collaborative research programme with the Ministry of Health and Sports of Myanmar. 

In addition, I am collaborating with the Texas A&M University in the USA, East China University of Science and Technology in People’s Republic of China, and Sabanci University in Turkey. 

I am also actively accepting international students and I strive to help them to become independent research leaders of the future. As a member of a collaborative programme between four Chinese universities, including China Medical University and Okayama University, I have been actively promoting the acceptance of international students (about 15 students per year) for 5 years. I have been awarded the Okayama Medical Association Award for these activities. 

In these endeavours, I have been privileged to act as a mentor to 15 international students, including those that came through programmes supported by the Embassy of the Islamic Republic of Pakistan and those of Surrey University in the United Kingdom. 

Improving the quality of scientific research by peer-reviewing for international academic journals – Aiming for the sound development of science 

I have reviewed 83 manuscripts for high-impact international journals, such as the British Journal of Pharmacology, Clinical and Translational Medicine, and eLife. In this way, I have contributed to the development of science by helping to improve the quality of submitted papers. My track record as an expert reviewer is available on Publons web-site operated by Clarivate Analytics. More than 20 manuscripts that I have reviewed have been published and contributed to the development of human knowledge. 

In addition to being an Editorial Board member in five international academic journals, such as Pathophysiology, I am also involved in the publication of academic research as a guest editor for special issues of international academic journals, whereby I also contribute to the development of scientific knowledge. 

Furthermore, as a member of the Certified Clinical Research Review Committee of the Ministry of Health, Labour and Welfare of Japan, I have reviewed more than 200 clinical research proposals at my institution, the Okayama University. Through this effort, I am contributing to the sound implementation of human clinical research. 

RESEARCH PROGRAMME AND ITS POTENTIAL FOR SCIENTIFIC IMPACT 

Goals of the current research programme 

The goal of my current research programme is to elucidate the effects of TRPM4 channel activity on human ischemia-reperfusion injury. When reperfusion occurs after a period of interruption of blood flow, all organs, including the brain, lung, liver, kidney, and intestine, are damaged by the accumulated reactive oxygen species. This is the main cause of organ injury after organ transplantation and is also a cause of stroke. The goal of my research is to clarify how TRPM4 channel activity affects these conditions. 

Specifically, in my research, I aim to reproduce models of the heart, brain, and kidney on the organ-on-a-chip platform, using human cells, and to elucidate the involvement of TRPM4 channel activity in the ischemia-reperfusion injury in each organ model. 

Furthermore, tissue damage due to the ischemia-reperfusion injury can be regarded as a process of cell death due to oxidative stress. Therefore, the extended goal of this study is to elucidate the effects of TRPM4 channel activity on the process of cell damage due to oxidative stress that occurs in conditions such as aging and ischemia-reperfusion injury. 

Outline of the breakthrough nature of the research and how this will advance the field 

The research of my team is very novel and original in that it reveals the effects of a previously unconsidered protein, TRPM4 channel, on the extremely important phenomenon of human cell death. Our work has the potential to uncover common mechanisms of cell death following ischemia-reperfusion injury in various organs and change our understanding of cell death. 

An overview of the research programme and timelines for the project 

We have already developed organ-on-a-chip models of the heart and kidney using human cells. In addition, a method for knocking out the TRPM4 gene in human iPS cells using CRISPR/Cas9 has already been established. 

We will develop an organ-on-a-chip model of the brain in 2021. Two methods will be used to simulate ischemia-reperfusion injury: the administration of hydrogen peroxide and hypoxia/reoxygenation treatment. We will validate these methods in 2021. 

In 2022, we will compare the extent of cell injury, production of reactive oxygen species, and changes in the intracellular calcium ion levels due to ischemia-reperfusion between the TRPM4 knockout group and the control group. 

As a more challenging task, we will analyse the effect of TRPM4 channel activity on organ damage by perfusing human blood into the organ-on-a-chip models to cause ischemia-reperfusion injury in 2023. 

RESEARCH PROGRAMME AND ITS POTENTIAL FOR IMPACT ON THE GLOBAL CHALLENGES 

Elucidation of the mechanism of cell death following ischemia-reperfusion injury and oxidative stress will have a great impact on improving human health in addition to advancing basic scientific knowledge. For example, tissue damage that occurs after transplantation of organs, such as the kidney, myocardial infarction, and cerebral infarction, which are pathologies with large global incidence, are caused by the ischemia-reperfusion injury. Our experiments are expected to have a tremendous impact on improving the condition and the quality of life of patients. 

Our previous studies have shown that TRPM4 channel inhibition reduces cardiac ischemia-reperfusion injury in rats and in cultured cells. Currently, my research team is using the organ-on-a-chip experimental system built of human cells to show that inhibition of TRPM4 channels reduces tissue damage in ischemia-reperfusion injury of the heart, brain, and kidney. 

Although it is difficult to accurately quantify the effect of ischemia-reperfusion injury on the symptoms of myocardial infarction and cerebral infarction, it is relatively easy to quantify the degree of renal injury following kidney transplantation. The annual number of kidney transplants per million in 2016 was 79, 64, 62, 59, and 54, respectively, in Mexico, Spain, the United States, the Netherlands, and France. The support to our research programme that investigates the ways to minimise renal dysfunction after kidney transplantation, may increase the chances of many patients to lead a healthy life. 

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Takahashi Lab at Okayama University uses principles of physiology, cellular and molecular biology, and biophysics. The purpose of the lab is to develop science and medicine by unveiling the mechanisms of diseases through collaborations with scientists, epidemiologists, and corporate alliances. The alliance includes Harvard University, Boston University, Tokyo University of Science, and PD Aerospace, Ltd.

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