- Biochemistry. Protein function analysis. Identification of protein-protein interactions.
- Development of imaging technologies for observation of energy metabolism in vivo
- Identification of disease-related genes and elucidation of pathology by biochemistry
- Drug screening system for disease-related genes
Linking small biological events to whole body function for better understanding of pathologies and improved disease treatments.
The heart is required to respond promptly to the constantly changing demand of blood supply and consumes the most energy (ATP) of all organs in the human body. Last year, we reported the discovery of a novel regulatory molecule, Higd1a, which is involved in mitochondrial energy production . Higd1a is induced under hypoxic conditions and binds to Complex IV (cytochrome c oxidase) of the mitochondrial respiratory chain to increase energy production efficiency. Mitochondrial energy production using oxygen is a fundamental mechanism in higher organisms, and it is known that abnormality in such function manifests various organ disorders such as neurodegenerative diseases and mitochondrial diseases. Currently, we are working on the development of drugs that act on Higd1a to enhance the activity of cytochrome c oxidase. According to the biochemical analysis of complexes responsible for oxidative phosphorylation in mitochondria, which is the main process of ATP production, our laboratory established a technique to visualize cardiac mitochondrial ATP kinetics in vitro and in vivo, and identified a regulator of ATP production, G0S2 . We are further elucidating the regulatory mechanism of ATP production by G0S2 protein and a proteolytic control mechanism, and at the same time, constructing a unique compound screening system targeting G0S2 protein and other drug candidate compounds that enhance ATP production.
Severe heart failure, the terminal condition of heart disease, remains a major medical and social issue. Currently, only a small proportion of severe heart failure patients have access to effective medical care. In our laboratory, we discovered the world’s first cardio-specific myosin light chain kinase by analyzing tissue samples of heart failure patients . Phosphorylation of cardiac myosin light chain is a known physiological factor that enhances myocardial contractility and exerts cardiotonic action without the activation of neural or humoral factors or elevation of myocardial oxygen consumption. Therefore, we are developing compounds with multiple protein targets that control the phosphorylation state of myosin light chain. Unlike traditional cardiotonic drugs, we aim to develop a new type of oral cardiotonic drug that can improve the daily living of patients with severe heart failure.
1. Proc Natl Acad Sci U S A. 2015 Feb 3;112(5):1553-8.
2. Proc Natl Acad Sci U S A. 2014 Jan 7;111(1):273-8.
3. J Clin Invest. 2007 Oct;117(10):2812-24.