Kobe UniversityKyoto UniversityOsaka University

Dr. Atsuhiko ICHIMURA

Atsuhiko ICHIMURA

Atsuhiko Ichimura, Ph.D.

Biopharmacology
Program-Specific Assistant Prof. of the Graduate School of Pharmaceutical Sciences at Kyoto University
Completed the doctoral course in the Graduate School of Pharmaceutical Sciences, Kyoto University, in 2011. Worked in Tohoku University School of Medicine, and assumed a post in Kyoto University in 2014. Appointed to current position in October 2015.
Research Overview

From elucidating cellular level stress to responses application in drug development and therapeutics

Organisms are exposed daily to various kinds of stress: stress attributable to the external environment such as excessive intake of energy and hypoxia and stress on the cellular level attributable to the internal environment such as unbalanced charge distribution in cells and abnormal pH. For an organism, mechanisms for responding to such stresses and maintaining homeostasis are crucial, and failure of such mechanisms leads to various diseases, sensors for detecting changes in the environment play an especially important role in the mechanism. I’m working to elucidate the functions of cellular receptors, which act as sensors, to understand the pathology manifested by abnormality of the receptors and to contribute to the development of novel drugs.

Sensor of fatty acids in the body – Fatty acid receptors

The fatty acid receptor is one of the molecules that have recently been found to act as a stress response sensor. Fatty acids were believed to be merely a source of energy, but were discovered to transmit various signals into a cell by binding to fatty acid receptors. The signals are likely to regulate the metabolism of the whole body upon exposure to stress, such as excessive intake of energy and starvation, by inducing physiological functions such as 1) stimulating secretion of insulin, GLP-1 or another peptide hormones that control blood sugar level and induce take up of glucose from the blood, and 2) storing fat by stimulating the differentiation and maturation of adipocytes.

I have mainly worked on GPR120, a receptor of mid- to long-chain fatty acids including α-linolenic acid and DHA. When knockout mice that lacked the GPR120 gene were fed a high fat diet, the mice showed increases in the weight of the liver and white fat. From this, we found that the GPR120 knockout mouse was prone to gaining weight from a high fat diet and developing abnormal carbohydrate metabolism. The same was also found to apply to humans. In a French international joint study that involved examining the genome of about 10,000 obese and non-obese individuals, the obese group was found to have a higher probability of having a mutation of GPR120 compared to the non-obese group. The data suggests that persons with a genetic loss of mutation in GPR120 have a tendency to gain weight easily.

I am planning to perform a precise analysis on how GPR120 and a series of other fatty acid receptors, whose functions in each organ have not been unveiled, control the energy metabolism of the whole body by using mice that lack the genes only in specific single organs. Elucidation of these molecular mechanisms and control by using low-molecular weight compounds are expected to lead to the development of new drugs for metabolic diseases such as obesity and diabetes.

TRIC channel regulating the calcium signaling within a cell

Cellular functions are maintained by proper transfer of materials, such as metal ions and proteins, into and out of cell organelles such as the nucleus, endoplasmic reticulum and Golgi apparatus. However, this material transfer can generate a large potential difference across the organelle membrane, imposing a stress so severe to the cell that the cell cannot manifest its proper physiological functions. There are sensors within cells that regulate stress caused by material transfer.

I am investigating the TRIC (trimeric intracellular cation) channel on the endoplasmic reticulum membrane whose physiological function was unveiled some years ago. The endoplasmic reticulum (ER) is a cellular organelle in charge of synthesis and modification of proteins and lipids. It also has another important role to store and release calcium. Calcium release induces control of gene transcription and leads to the manifestation of various physiological functions. During the process, two positive charges are released per one calcium ion, generating a potential difference across the endoplasmic reticulum membrane, hindering continuous release of calcium. The TRIC channel transports positive ions back into the ER to mitigate the potential imbalance between the ER and cytoplasm and to support normal calcium release from the ER.

Malfunction of the TRIC channel causes excessive accumulation of calcium in the ER, finally leading to ER stress which may cause disorders. One of such a disorder is dysostosis. It has been recently reported that a few pedigrees with a mutation in the TRIC-B gene, one of the two TRIC channel subtypes, develop inborn dysostosis. However, it is unknown how the mutation of the TRIC channel is involved in the pathology. I am analyzing how the TRIC-B deficiency affects osteoblasts, osteoclasts and cartilage cells, which are involved in bone formation, by using knockout mice lacking the TRIC channel gene. I’m aiming to elucidate the precise molecular mechanism and demonstrate potential for developing drugs mitigating TRIC channel abnormalities.

From elucidation of pathology to drug development

I’m currently performing fundamental research from the viewpoint of cellular responses to stress but will move to studies for using the knowledge in drug development. I’m also performing application studies targeted at proteins induced by stress such as inflammation and hypoxia by using low-molecular weight compounds. I believe drug development studies at universities should play an important role in elucidating the underlying mechanisms and developing clinically applicable drugs for rare diseases, which are difficult for the drug industry to engage in. I will actively use diverse approaches in both fundamental and application research jointly with experts from different fields such as medicine and engineering to elucidate unknown pathology and contribute to the development of new drugs.