Hokkaido University Research Profiles

Life Sciences

Development of Therapeutic Agents and Biomarkers for Stress-induced Diseases

Molecular psychoneuroimmunology to understand the molecular mechanism of “disease starts in the mind”

Chronic stress has become a widespread problem in our society as it may lead to sudden death or other serious problems due to overwork or insomnia. We have clarified the molecular mechanism by which chronic stress induces organ damage and sudden death in mice through the activation of specific neural circuits. This system can be used to search for therapeutic targets for stress-induced diseases.

Content of research

We are studying the link between stress and disease. Recently, when autoreactive T cells against central nervous system antigens were transferred to mice that had been subjected to chronic stress, the mice suddenly died. The cause of death was heart failure due to hemorrhage in the stomach and duodenum, as found with humans. Stress-specific activation of neural circuits induced microinflammation in the brain, where transferred T cells, etc. were accumulated in specific blood vessels, and a new neural circuit activated by this triggered the gastrointestinal disorder and heart failure. There have been no animal model of stress in which the molecular mechanism has been elucidated, and this model is useful for screening of new drugs for stress-induced diseases. Using this system, we also identified a group of molecules of which the expression is upregulated in specific blood vessels in the brain during stress, and antibodies against these molecules suppressed sudden death. We are also currently identifying marker candidates for autoreactive T cells in humans.

  • Chronic stress activates the sympathetic nervous system in the paraventricular nucleus (PVN) (1), and a protein called chemokine is produced in specific blood vessels on the border of the third ventricle, thalamus and hippocampus. Autoreactive immune cells that recognize central nervous system antigens present in the blood then cross the blood-brain barrier and accumulate around this specific blood vessel, inducing microinflammation. This triggers the activation of new neural circuits (2) to (5), which induce inflammation in the upper gastrointestinal tract, including the stomach and duodenum, and result in sudden death due to cardiac dysfunction. A new breakthrough finding of this study is that microinflammation in specific blood vessels of the brain induces dysfunction of peripheral organs by inducing the activation of new neural circuits, which we call the stress gateway reflex. A variety of drugs have already been tested in this experimental system, and examples of drugs that prevent gastrointestinal bleeding and sudden death and their sites of action are shown below.
    We have already identified a group of genes of which the expression is upregulated in specific blood vessels in the brain under stress, and six of these genes (C2CD4D, VSTM2L, VSTM2A, TMEM5, LY6G6C, and ADRA2C) were suppressed by antibodies, which thus suppressed sudden death after stress.

Potential for social implementation

  • ・Drug screening for stress-induced diseases
  • ・Search for new drug targets for the above diseases
  • ・Development of biomarkers to predict stress sensitivity
  • ・Application to diseases associated with microinflammation in the brain such as dementia
  • ・Development of therapeutic agents for progressive multiple sclerosis

Appealing points to industry and local governments

This model has also identified a candidate target for antibody drugs, and will contribute to prevention and treatment strategies for stress-related diseases. Immune cells that induce microinflammation in the brain exist in humans, and the number of such immune cells varies among individuals. It is conceivable that people with many of these cells may be prone to stress-related diseases, and that these cells may serve as a good biomarker of stress sensitivity and a therapeutic target for stress tolerance induction.

Intellectual property related to this research

PCT/JP2018/007901 「疾患モデル非ヒト動物の製造方法、疾患モデル非ヒト動物、該動物を用いた薬剤のスクリーニング方法及び疾患リスク判定方法」
(日本:特願2019-503129 米国:16/490145)
PCT/JP2019/034497 「ストレス負荷が関与する疾患を予防及び/又は治療するための医薬」