Research projects

Our research focused on thrombin's role in the β1 integrin/phosphorylated myosin light chain (p-MLC)/actin pathway within the blood-brain barrier (BBB), revealing its contribution to vascular endothelial dysfunction during ischemic conditions. In collaboration with the University of Electro-Communications, we employed a middle cerebral artery occlusion (MCAO) model to demonstrate significant correlations between reduced cerebral blood flow, cortical spreading depression patterns, infarct volume expansion, and worsened neurological outcomes. While Evans blue extravasation assays showed inconsistent results in quantifying BBB permeability changes within this MCAO model, the study provided novel insights into cerebral microcirculation dynamics and ischemia-mediated barrier dysruption mechanisms.

A detailed survey of >200 patients with headache attending the outpatient headache clinic at Keio University Hospital was conducted using a questionnaire on approximately 50 candidate headache triggers. More than 75% of the patients were confirmed to be aware of stress, lack of sleep, and low barometric pressure as triggers, respectively. In addition, a survey on nursing staff at Keio University Hospital revealed that patients who usually have headaches are more likely to experience headaches after COVID-19 vaccination (Sekiguchi K et al. Cephalalgia 2022). We conducted a study using cortical spreading depolarization (CSD), an animal model of migraine, to verify whether smoking is a trigger of migraine. We found that CSD was more likely to be induced in female mice that were exposed to smoking, suggesting that they were more likely to develop migraine.

We reported real-world evidence on anti-CGRP monoclonal antibodies (CGRP mAb) at Keio University Hospital. The 50% response rate ranged from 40% to 60%, and the 100% response rate was approximately 10%. Characteristics of responders included older age, fewer failures with previous preventives, and no history of autoimmune diseases. Furthermore, a survey conducted among physician members of the Japanese Headache Society revealed that many physicians set stricter criteria for initiating CGRP mAb than those recommended in the guideline (monthly migraine days greater than or equal to 4, and failure of greater than or equal to 1 conventional preventive medication). As part of our investigation into novel treatments, we examined the effect of the antiepileptic drug lacosamide on cortical spreading depolarization, an in vivo model of migraine. We found that lacosamide had a suppressive effect in female mice.

我が国で頭痛やめまいの症状を持つ患者数は3,000万人を超えると言われており，それに伴う気分の揺らぎに伴うパフォーマンスの低下は，社会全体の活動低下を招いている．これらの患者のなかには，心的ストレスが原因となって身体の不調を訴える症例が多く含まれているが，なぜそのような身体化の症状が生じるかは十分に解明されていない．本研究では，健常者・身体症状症・片頭痛・メニエール病の患者を対象として，自律神経活動，身体状態の変化を感知する内受容感覚，予測的情報処理に基づく信念形成の特性に着目し，気圧変化に対する身体・認知特性を明らかにする．そして，症状改善に向けたプロトコルの開発に取り組む．

CGRP関連抗体薬が2021年に上市され、片頭痛診療は大きな変革期を迎えている。そのような中、わが国における頭痛・片頭痛の最新の疫学を明らかにすることは重要と考える。 片頭痛について、有用なバイオマーカーは確立されていない。 本研究では、頭痛・片頭痛についての疫学調査を実施する。さらには片頭痛のバイオマーカーの検索などを試みる。

We focused on NG2 glia to investigate morphological changes during cerebral ischemia and to investigate the mechanism of improvement of the pathological condition. We established a technique to track longitudinal morphological changes of various cells through a chronic cranial window by Tomita-Seylaz method using the genetically engineered mice expressing fluorescent protein in Sox10, highly coexpressing with NG2, and revealing in oligodendrocytes and their progenitor cells. We tracked morphological changes in various cells by repeated observation using two-photon microscopy for a long duration. Further, we established the middle cerebral artery occlusion technique and found that the occurrence of cortical spreading depolarization is involved in the formation of infarct foci after transient occlusion of cortical branches, and that tissue damage associated with reduced striatal blood flow due to transient occlusion at the origin is involved in the development of neurological deficits.

頭痛患者は極めて多く、痛みや気分の揺らぎによるパフォーマンス低下は社会的損失を招いている。頭痛患者の中には「予測」が引き金となる心理的痛みを持つ者が多く含まれ、特に気圧変化との関連が注目されるが、気圧変化の数日前から頭痛が生じるメカニズムは未解明である。本研究では、気圧カプセルを用いた自律神経の予測機能と頭痛の関係を調べる実験と、独自アプリによる気圧変動と頭痛の観察研究を通じて、生理的痛みと心理的痛みの分離を目指す。気候変動が心身に及ぼす影響の研究が遅れている現状を打破し、治療抵抗性と扱われドクターショッピングに陥る患者の原因解明と、臨床的に適切な指針の提供を目指す。

一部の遺伝性脳小血管病では、基底膜を構成するアミノ酸が他のアミノ酸に置換され、コラーゲンの三重らせん構造が崩れることが原因でラクナ梗塞、白質病変など脳小血管病変をきたす。ただし、その機序の詳細は解明されていない。我々はこれまでに、コラーゲンIVの受容体であるβ１インテグリンの機能阻害やコンディショナルノックアウトにより、遺伝性脳小血管病と同様の血栓形成、出血性変化、白質病変の原因となる血液脳関門の破綻が惹起される現象とその機序を報告した。本研究はコラーゲンIV変異による血液脳関門の障害機序を評価するとともに、血管内皮細胞内シグナルの調節に基づく遺伝性脳小血管病の治療確立を目標とする。