Development and Application of Cell Death Control Molecules

2018 Fiscal Year Final Research Report

• Project Area: Homeostatic Regulation by Various Types of Cell Death
• Project/Area Number: 26110004
• Research Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Institute of Physical and Chemical Research
• Principal Investigator: SODEOKA Mikiko 国立研究開発法人理化学研究所, 開拓研究本部, 主任研究員 (60192142)
• Co-Investigator(Kenkyū-buntansha): どど 孝介 国立研究開発法人理化学研究所, 開拓研究本部, 専任研究員 (20415243)
• Project Period (FY): 2014-07-10 – 2019-03-31
• Keywords: 細胞死 / ネクローシス / 構造活性相関 / 有機化学 / 酸化ストレス

Outline of Final Research Achievements

In general, cell death is classified into two major categories, apoptosis and necrosis, according to its morphological features. Apoptosis is associated with characteristic and regulated morphological changes, but necrosis results in cellular swelling and rupture of cell membrane, which could be induced by accidental physical injury. Therefore, only apoptosis was believed to be regulated, and necrosis had been considered as uncontrolled and accidental cell death. However, recent studies have revealed novel mechanisms for controlling necrosis.
We previously developed indolylmaleimide (IM) derivatives as novel inhibitors for oxidative-stress-induced necrosis. In this study, we have revealed unique cell death inhibition profile of IM derivatives and developed a water-soluble IM derivative IM-17, which showed cardioprotective effects in ischemia-reperfusion injury.

Free Research Field

ケミカルバイオロジー

Academic Significance and Societal Importance of the Research Achievements

本研究は、古くは制御されない細胞死として研究対象とされて来なかったネクローシスに新たにスポットライトを当てた点、またその作用機序に独自に開発した阻害剤を用いてアプローチする点に学術的意義がある。さらに、虚血性心疾患を含む心疾患は、現在我が国のがんに続く第2位の死因となっており、IM化合物が虚血性心疾患に治療効果を示したことの社会的意義は高い。IM化合物はその治療薬リードとして期待されると共に、その作用機序解明により新たな治療法の開発にもつながる可能性が考えられる。