2018 Fiscal Year Final Research Report

Roles of gaseous mediators in the regulation of vascular and neural functions

Research Project

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Project/Area Number	16K07066
Research Category	Grant-in-Aid for Scientific Research (C)
Allocation Type	Multi-year Fund
Section	一般
Research Field	Neurochemistry/Neuropharmacology
Research Institution	Keio University
Principal Investigator	KAJIMURA MAYUMI 慶應義塾大学, 医学部(日吉), 教授 (10327497)
Research Collaborator	GOTO Shinichi MORIKAWA Takayuki HISHIKI Takako KUBO Akiko
Project Period (FY)	2016-04-01 – 2019-03-31
Keywords	一酸化炭素 / Heme oxygenase / 質量分析イメージング / Neurovascular coupling / エネルギー代謝
Outline of Final Research Achievements	Brain generates carbon monoxide (CO) via heme oxygenase (HO) reactions. We examined the hypothesis that deletion of HO-2 exacerbates energy metabolism during acute brain ischemia. We conducted quantitative imaging mass spectrometry analysis to decipher local energy metabolism from wild-type (WT) and HO-2-null mice that underwent a 60-min occlusion of the left middle cerebral artery (MCAO). In ipsilateral hemispheres, MCAO caused elevation of AMP, ADP, and lactate, and depletion of ATP in both WT and HO-2 null mice. Ischemic core was larger in HO-2-null than WT mice. Striking differences were found in the contralateral hemispheres, where levels of ADP, AMP and lactate in HO-2-null mice were higher than those in WT mice. It suggests that the HO-2/CO system plays roles in protecting against ischemia not only at ischemic cores where severe reduction of blood flow occurs, but it also protects effectively in trans-hemispheric regions where only a subtle reduction of blood flow takes place.
Free Research Field	代謝生化学
Academic Significance and Societal Importance of the Research Achievements	研究対象とした脳循環代謝病態においては、ATP産生を支える基質供給機構の同定など、エネルギー代償機転の分子機構の解明が大きな課題である。ガス分子の作用点を代謝物のin vivo-profilingにより空間的・定量的に解析することにより、これまでのin situの系では捉えにくかったセンサー蛋白とシグナル分子の相互作用を、直接的に構築できる可能性を有する点において本研究は独創的である。研究成果は、脳循環障害や神経疾患の病態を理解し、治療のターゲットを絞りこむための布石となりえ、救急蘇生学などの臨床医学研究への波及効果が期待される。