COVID-19やインフルエンザが重症化すると、重篤な呼吸不全 (ARDS)や多臓器不全が引き起こされ。一方、急性期の症状が回復した後も、長期間複数臓器にまたがって罹患後症状（後遺症）が発症する。これらには、ウイルス側の因子に加え、ヒト側の遺伝的因子に加え、加齢や基礎疾患等に関係したエピジェネティックな因子が、多彩な病態の形成につながっていると考えられる。われわれは、感染患者から診療情報や検体を収集し、マルチモーダルな医療ビッグデータを生成し、これらを用いて重症化を予測可能な機会学習モデルを構築した。また培養細胞やマウスの感染系を用いた基礎的検討を通して、ウイルス感染に伴って後天的エピゲノム修飾状態がダイナミックに変化し、これが感染病態の形成に関わっていることを明らかにした。さらにフレイル、うつ、認知障害等の後遺症を起こすマウスモデルを樹立し、病態、創薬標的を同定した。今回、これらのウイルス感染に対する生体システムの作動原理、創薬の可能性について、われわれの知見を中心にお話したい。

2019年の暮れ、中国武漢に新型コロナウイルスが出現し、世界中に伝播し、多大な被害をもたらしました。私達は、本ウイルスに対する予防や治療法の確立を目指して、様々な研究を行っています。本シンポジウムでは、動物モデルの確立や変異株の性状解析など、これまでに得られた成果について御紹介させていただきます。

SHIONOGIは、感染症のリーディングカンパニーとして、HIV、インフルエンザ、AMR（薬剤耐性）、COVID-19といった感染症に対する新薬の研究開発に取り組んできました。本講演では、SHIONOGIがこれまで取り組んできた感染症領域での活動に加え、今回のパンデミックで学んだ「感染症に対する備え」の重要性と理想とする姿について述べさせていただきます。まずは、当社がどのように医療への貢献に取り組み、多くの製薬企業が撤退した感染症領域の研究開発に注力し続けてきたのかをご紹介します。その中で、COVID-19治療薬の開発で直面した課題や困難についてご紹介し、「平時からの備えの必要性」と「日本における有事対応の強化」（SCARDAの設立、緊急承認制度の創設など）について共有させていただきます。今後、日本においては、産官学が一体となりこの新たな仕組みや制度を運用することで、有事対応力の向上が期待されますが、その実現には、産官学が「共通の方向性」を持つことが重要ではないでしょうか。本講演が、その「共通の方向性」を考える上で、少しなりとも参考になれば望外の喜びです。

タケダの240年以上にわたる歴史は、患者さんの暮らしと社会を豊かにすることを目指す行動の積み重ねによって築き上げられてきました。常に患者さんに寄り添うことを第一に考え、そのうえで人々との信頼関係の構築、社会的評価の向上、事業の発展という順番で日々考え、行動することがタケダを際立たせていると信じています。 近年タケダは、研究開発主導型のグローバルなデジタルバイオ医薬品企業として劇的に競争力を高めています。グローバルな事業展開、強固な財務状況、バランスのとれた製品ポートフォリオ、そしてタケダで働く多様な人材が世界中の患者さんに革新的な治療法をお届けすることを可能にしています。研究開発の変革を通じて、明確に定義された疾患領域に焦点を当て、小分子にとどまらずモダリティを多様化し、内部の研究能力と外部との協力関係を強化することで、患者さんと社会により意義のある貢献を果たしています。 現在の診療報酬モデルに基づく医療制度は、寿命が延び、人口が高齢化し、革新的な治療法が拡大する中で大きな負担に直面しています。この負担を緩和するため、治療結果に焦点を当てた患者さんを中心とするアプローチがこれまで以上に重要となっており、結果と質に対する支払いを行うバリューベースヘルスケア制度へ早急に移行する必要があると考えています。そのため、タケダのグローバル成長戦略は、ベストインクラスまたはファーストインクラスとなる可能性が高い革新的な医薬品に重点を置いています。また、外的要因によるリスクへの準備と対応力を強化するとともに、従業員のスキルを向上し、さらなる価値創造を加速させるべく、データ、テクノロジーやAIへの投資も進めています。 従業員にとって理想的な働き方の実現にもコミットしています。当社の治療薬を必要としている患者さんの視点を反映し、従業員の多様性を尊重し育んでおり、個人の性別、年齢、国籍などの属性にかかわらず、従業員が能力を最大限に発揮し、生き生きと働ける環境づくりに努めています。

With particular relevance to the COVID-19 pandemic, Josef Penninger will presenthow work on ACE2 and its role in lung failure, from the discovery in fly heartdevelopment to the first mutant mice and a fundamental understanding of SARSCoronavirus. This data provided the first molecular underpinning why the firstSARS-CoV and now SARS-CoV2 causing COVID-19 became "dangerous viruses". ACE2 isthe critical receptor for SARS-Cov-2 and has taken center stage in globalresearch and drug and vaccine development. This work has also been translatedinto ACE2-based drugs as rational and universal prevention and treatmentstrategies for COVID-19.

本講演では、講演者らが内閣府／JST ムーンショットプロジェクト目標２で行っている、「複雑臓器制御系の数理的包括理解と 超早期精密医療への挑戦」に関する研究の成果を基にして、いのちと科学をむすぶ未病創薬の基盤となる数理的研究を紹介する。特に、健康状態からの逸脱の兆候の鋭敏な数理的検出、発病前の未病状態に固有のゆらぎを検出するDNB（動的ネットワークバイオマーカー）理論、さらには未病状態を治療するための制御理論などを詳しく説明する。

バイオ医薬品は抗体にとどまらず、モダリティの種類を確実に増やし、次世代医療に貢献している。創薬モダリティとしての抗体は、バイオ医薬品の先頭走者として、ますますその活躍の場を広げている。最近では、抗体分子に新たな機能を付与した次世代型の抗体医薬品の研究開発が進められている。例えば、低分子化合物を付加する抗体薬物複合体（ADC）、複数種類の部分構造をミックスして構築する多重特異性抗体、ラクダ科由来VHH抗体、などが近年特に注目を集めている。いずれも、すでに用いられている抗体医薬品の適用範囲を拡大させるものである。これらは、既存の要素技術を組み合わせた展開、あるいは情報科学を活用した方向性を多く含んでいる。ここでは、以上のような、イノベーションを取り込みさらに発展する抗体工学を中心に、新時代の創薬モダリティについて議論する。

本講演では近年になってますます進展の著しいゲノム関連技術の潮流と、我が国での今後のゲノム研究の方向性について論じたい。まずシングルセル解析から端を発した空間解析の瞬く間の普及について振り返る。先行するシングルセルの成熟は、さらにその元を辿れば次世代シークエンサーのシークエンス能力の飛躍的な拡大と普及がある。何万、何十万人にといった規模でヒト全ゲノム解析を行える性能がなければ、何万、何十万細胞についての遺伝子解析を行うことは不可能であった。しかし、これが空間位置情報を保全した形での遺伝子発現解析へと変貌を遂げるにあたりシークエンスに依存しない計測へと大きな変貌を遂げつつある。ここでは産出されるデータは、塩基配列データではなく画像情報を主とする。必然的にこれまでのデータ利活用、データベースの在り方も大きな転換点を向ける。10年にわたって広く医学・生物学分野を席巻した次世代シークエンス時代のひとつの転機として、現在のゲノム科学の新しい勃興期の熱狂を参加者の皆様と共有したい。あくまで演者の立場からの一方的情報提供の場でなく、会場全体での意見交換の場となれば、と思う。

真核細胞は、核と細胞質が核膜によって隔てられており、細胞が生きるためには、核膜に存在する核膜孔を通して、機能分子が核と細胞質間を効率よく正確に輸送されることが必須である。従って、その輸送の分子メカニズムを解明することは、様々な生命現象を理解する上で極めて重要であり、医学・薬学の発展にとって必須の研究テーマである。本講演では、先ず、核―細胞質間蛋白質輸送に必須の因子であるimportin alpha/betaの発見など、生命科学史に残る重要な発見を通して、核蛋白質輸送の基本メカニズムの理解がどのように進められたかを説明する。さらに、それらの輸送因子が、細胞分化、発生、ストレス応答などの複雑な生命現象の理解にどのように貢献したかを解説する。また、核輸送装置が、細胞のがん化や老化などにも深く関わってくることが明らかになり、それらを標的とした創薬への展開が進められている。このように、本講演では、基礎的な細胞生物学的研究が、どのようにして医学・薬学の発展に貢献していくかを概説したい。

個体が発生する際に、受精卵はまず各々の組織の幹細胞を産み出し、 その 組織幹細胞が主軸となって様々な種類の細胞を作りだし機能的集団を作りだす。 組織幹細胞は、発生の間、未分化なまま増殖しながら、かつ一方で色々な分化細胞を産み出しその組織を構築する、という非常に興味深い細胞である。 では、どうやって幹 細胞は適切に増殖と分化を制御し秩序だった組織を形成できるのだろうか? 特に神経系という組織においては、神経回路の素子である様々な種類のニューロンやグリア細胞を「正しい場所に」「正しい数」配置することが 機能的なネットワークを作 る前提として必須である。したがって、神経幹細胞の運命がどのように制御されるかが、 この複雑で精巧な脳という組織を正しく作り上げるための鍵を握っていると言え る。本講演では神経幹細胞のニューロン分化能の基盤となるクロマチン因子に焦点を当てて、脳発生における細胞運命選択メカニズムの一端をご紹介したい。

また、もし時間が許せば、ウイルス感染の初期応答における細胞の運命選択メカニズムについてもお話ししたい。

DNAシークエンス技術やさまざまなオッミクス解析技術の進歩に伴い、サイトカインやケモカインなどの生理活性物質、T細胞・B細胞受容体配列解析などを経時的に捉えることが可能となり、多種多様な病態や薬剤の応答性に関連する免疫細胞の変化を詳細に追跡することができるようになりました。また、シングルセルレベルでの解析技術も進み、ダイナミックな免疫系細胞の動きを詳細に知ることができるようになりました。さらに、薬物誘発性の皮膚過敏症や肝毒性は、薬物とHLAの相互作用によって活性化された免疫応答が重要なカギを握ることが示唆されています。スチーブンス・ジョンソン症候群などの薬疹にはHLAのクラスI分子が、肝毒性にはクラスII分子が関連しています。がん治療においては、がん組織内や全身の免疫環境が、がん免疫療法だけでなく、抗がん剤・分子標的薬の反応性においても重要であることがわかってきています。さまざまな疾患の発症・寛解・増悪過程での免疫応答の変化は、これまで完全に解析されていませんでしたが、免疫薬理ゲノム学の発展はこれらの解明に重要になってくることを紹介します。

世界初のアルツハイマー病（AD）疾患修飾薬「レケンビ」が米国に次いで本年9月に本邦で承認され認知症治療は新たな時代を迎えた。ここまでエーザイは40年以上にわたって認知症領域で研究開発を続けてきたが、それは失敗を乗り越えリスクを分散させる工夫の連続であった。1997年に「アリセプト」を発売し世界初のAD薬の開発に成功したが、その後次世代の創薬を目指す日々が続いた。ADの根本原因であるアミロイドβ（Aβ）カスケード仮説に基づいた様々な新薬候補品を開発するもドロップが相次いだ。その中でアカデミア連携による家族性AD研究の成果を活用し、慎重な臨床研究により創薬したテーマが抗Aβプロトフィブリル抗体「レケンビ」であった。創薬は失敗なくして成功はない、失敗に耐えていると経験知が蓄積されていく。この経験知こそが創薬における成功の要諦であり、新薬開発という名の船を正しい針路へと導いてくれる「海図」となる。そしてその海図を書き込み、ナビゲートするキャプテンの存在も欠かせない。この機会に、AD当事者との共感の上に存在する「創薬精神」について触れたい。

統合失調症は10代後半から30代にかけて発症する重篤な精神疾患であり、主な症状は幻覚妄想などの陽性症状、感情平板化などの陰性症状と認知障害である。統合失調症の病因は不明であるが、遺伝的要因と環境要因が寄与している。現在、統合失調症治療薬として承認されている抗精神病薬は、陽性症状を改善するものの陰性症状や認知障害には効果が乏しく、難治例も多い。錐体外路障害などの重篤な副作用も問題となっている。したがって、病態解析に基づく新規治療標的の同定と疾患修飾薬の開発は喫緊の課題である。我々はゲノム解析に基づくトランスレーショナルリサーチによりこの難題に挑戦している。具体的には、日本人患者を対象としたゲノム解析の結果、病態パスウェイの一つとして低分子量Gタンパク質シグナルが示唆されている。我々は、統合失調症の発症に強く関与するARHGAP10遺伝子バリアントを同定し、このバリアントを模したArhgap10遺伝子改変マウスを作製・解析した。本講演では、これまでに得られたArhgap10遺伝子改変マウスの病態解析の結果とともに、Rhoキナーゼ阻害薬の抗精神病薬様作用について紹介する。

エピジェネティクスは個体発生をはじめとする様々な生命現象を制御するゲノムの高度活用戦略である。その分子的な実体は、染色体の複製や細胞分裂を経て維持されるDNAやヒストンタンパク質の各種修飾とそれらに基づく高次構造変化であり、これが発生過程における細胞の運命決定や、分化後の細胞の恒常性維持を担っている。一方、ランダムX染色体不活性化のように偶然性を取り込むエピジェネティックな現象もあるし、胎児期や発達期の環境ストレスによって誘導されたエピジェネティックな変化が、その個体の一生にわたる疾患感受性に影響を与える場合もある。すなわち、遺伝と環境の間をつなぐ分子的なメカニズムがエピジェネティクスである。また、通常は世代ごとにリセットされるエピジェネティック修飾の一部が、何らかの異常により次世代へ伝わるエピジェネティック伝達も報告されている。本講演ではエピジェネティクスの基本的なメカニズムに触れつつ、早期ライフステージにおける環境ストレスがエピジェネティクスを介して健康に及ぼす影響について紹介する。

我々はこれまで、RNAスプライシングパターンの変化を生体内で可視化する独自の技術を開発し (Nature Methods 2006)、このスプライシングレポーターを使って異常RNAスプライシングを是正できる化合物を探索する独創的創薬戦略によって、家族性自律神経失調症 (Proc Natl Acad Sci 2015, Nature Commun 2021)、デュシェンヌ型筋ジストロフィー (Nat Commun 2011)、嚢胞性線維症 (Cell Chem Biol 2020)、QT延長症候群などに対し、有効な治療薬候補化合物を見出すことに成功している。また、これらのスプライシング制御化合物で、がん細胞内のスプライシング環境にバイアスを与えることによって、スプライスネオ抗原を人工的に産生誘導出来ることを報告した（Science Transl Med,2022、PCT/JP 2021-144961）。スプラシング異常に起因する遺伝性疾患保因者に対し、我々が開発してきたスプライシング制御化合物により治療可能な対象者をゲノム情報からAIにより選択する技術を確立することによって、遺伝病や遺伝性がんの個別化に道を拓ける可能性がある。

臨床応用されている医薬品の薬理作用は判明したごく一部のメカニズムだけが教科書等で紹介されていると考えた方が良い。事実、開発段階においてすべての受容体・酵素・チャネルに対する親和性を測定しているわけではなく、ヒトにおける安全性も限られた例数と時間の範囲で調べられているに過ぎない。それを裏付けるように市販後調査によって判明する有害事象は後を絶たない。実際、臨床データの中には医薬品の未知なる作用が山のように埋もれており、その中には有害事象メカニズムだけでなく、思わぬ有益性も潜んでいると考えられる。では、どのようにしてそれを知ることができるだろうか？それを臨床リアルワールドデータ（RWD）から探し当てようとした我々の研究から今回いくつかの成果を紹介する。

（１）抗不整脈薬アミオダロンの服用によって肺組織の慢性炎症から線維化に繋がる間質性肺障害が起こるが、抗トロンビン薬ダビガトランの併用がその発症率を抑制することをRWDから見いだした。薬理学的検討から本作用はPAR1-PDGFRα-MMP12経路を抑制することによることが分かった。

（２）糖尿病治療DPP4阻害薬によって自己免疫疾患である類天疱瘡の発症リスクが高まるが、欧米で多用される降圧薬リシノプリルの併用はそのリスクを低減させることをRWDから見いだした。薬理学的検討から本作用は免疫細胞への作用ではなく、ACE2-MasR経路の抑制を介して皮膚MMP9の発現抑制によって類天疱瘡の発症を抑制することが示された。

（３）フルオロキノロン抗菌薬の投与はそれが短期間であれ、低頻度ではあるが腱障害リスクを高める。従来、治療ガイドライン等では副腎皮質ステロイド併用は腱障害リスクを高めるとされているが、RWD解析からはデキサメタゾンの予防効果が見いだされた。興味あることにデキサメタゾンは高齢者コホートにおける腱障害の自然発症率も抑制した。薬理学的検討から、フルオロキノロンは活性酸素種の発生を伴うDNA損傷によって腱細胞を障害するが、デキサメタゾンはラジカル消去に寄与するグルタチオンペルオキシダーゼGPX3の発現上昇を介して短期間では腱組織の機能に対して有益に働くことを見いだした。

トランスポーターは、生体内の物質分布を担う膜タンパク質であり、生体内のコンパートメント間のインターフェイスとして、各区画間の物質濃度比の決定に寄与している。したがって、トランスポーターの機能を薬物により制御することで、病態において異常となった物質分布をシフトさせ、生体の恒常性を回復させせることで疾患の治癒を促す。例えば、腎尿細管の糖再吸収を担うSGLT2（SLC5A2）の阻害薬はその例であり、糖の分布を尿側に傾け、それによって糖排泄を促進して高血糖を是正することで糖尿病治療薬となった。さらに、SGLT2阻害薬は、糖尿病でなくても心保護、腎保護等の臓器保護作用を示すことが明らになり、栄養素の体内分布制御のもたらす広範な影響を再認識させた。また、別の観点からのトランスポーターを標的とした栄養取り込み制御による創薬としては、例えば腫瘍細胞のような病態形成を担う細胞の活性を維持するトランスポーターも標的となる。悪性腫瘍においては、栄養素トランスポーターの発現が高まっており、特にがん細胞に高い特異性をもって高発現するアミノ酸トランスポーターLAT1（SLC7A5）が、診断、治療の標的として可能である。またLAT1は、特定の免疫担当細胞に発現が誘導され免疫系の過剰反応に寄与することも示されており、創薬標的として可能性が広がりつつある。トランスポーターを介する物質輸送は、酵素と同様に、輸送される物質の基質結合部位への結合が律速となり輸送過程が進行する。このため、トランスポーターの機能に干渉する薬物、特に競合阻害薬は、基質をもとに構造展開によって比較的容易に創製可能である。本講演では、演者らのLAT1を標的とした創薬研究を例に、トランスポーターと化合物の相互作用およびトランスポーターの創薬標的としての意義について議論したい。

脳の機能を改善・増強する現代的なアプローチは何だろうか。本講演では、ERATO池谷脳AI融合プロジェクトでの研究成果とその背景を説明しながら、脳と人工知能を接続することで何が実現できるのかを議論したい。

日本政府で進める医療DXのプロジェクト概要や構成される技術について解説し、諸外国の医療情報共有や解析等の2次利用事例を参考に、日本での課題と解決の方法を探ります。

神経発達障害（NDDs）は、神経発生発達初期に生じる神経系の障害によりもたらされる一群の複雑な疾患であり、自閉症スペクトラム症（ASD）、注意欠陥・多動性障害（ADHD）、知的障害、言語障害など複雑に絡み合った症状を示す。先進国においてNDDsの罹患者数は増加の一途を辿るが、根治的な薬剤はいまだ開発されていない。NDDsの病因病態解明を推進するためには、齧歯類等を用いた病態モデルの確立が重要であり、複雑な症状に合わせた多様なモデルが必要となる。遺伝学的解析より、これまでに多数のNDDsの責任・リスク遺伝子が同定されている一方、母体の薬物暴露、母体免疫活性化、父加齢などの環境的要因もNDDs発症の原因として知られる。また、NDDsの症状に合わせた解析系の開発も重要である。本講演では、演者がこれまでに解析してきたこれらの病態モデルを紹介するとともに、ビッグデータを用いて人工知能や機械学習を活用する新たな解析系についても言及したい。この講演を通じて、NDDsの病因病態解明に向けた最新の研究動向と方法論について議論し、遺伝的・環境的要因の複雑な相互作用をより深く理解し、有望な治療戦略の発展に寄与することを期待するものである。

我々は、眠気を記録している実体を明らかにするために分子活性の変動そのものが睡眠覚醒リズムを支配すると考え、哺乳類の睡眠（特にノンレム睡眠）について、神経細胞の活動パターンを直接担うイオンチャネル・ポンプについて、ノンレム睡眠時の神経活動の数理モデリングと、マウス睡眠表現型のスクリーニングシステム（SSS法）、独自に改良したCRISPRを用いたノックアウトマウス作製技術（Triple-CRISPR法）を用いて、細胞内Ca2+動態に直接関与する一連のイオンチャネル・ポンプが睡眠時間制御に重要であることを見出してきた。さらに細胞内Ca2+が制御するリン酸化酵素に着目しCamk2a/bノックアウトマウスが著明な睡眠時間の短縮を示すことを明らかにした。これはCaMKIIα/βが睡眠を誘導するリン酸化酵素であることを意味する。我々は睡眠誘導性リン酸化酵素CaMKIIα/βの発見を元に、神経細胞の興奮持続やエネルギーの枯渇、外的環境変化によるストレスなどの細胞状態・個体状態の履歴をリン酸化を中心とした分子修飾として統合・記録し、神経細胞の興奮性の低下、代謝活動の制御、ストレスによる細胞障害の修復を誘導する睡眠のリン酸化仮説を提唱するに至った。本講演では、動物を用いた睡眠研究の現在を解説するとともに、ヒトにおける睡眠・覚醒リズム研究の現在や未来のシステムに基づく医学（システム医学）の実現に向けた試み、特に睡眠健診の実現に向けた取り組みについても議論したい。

Biological membranes such as plasma membrane are formed by a phospholipid bilayer. Phospholipids have two fatty acyl chains attached to them, and these fatty acyl chains vary from saturated fatty acids to highly unsaturated fatty acids. The hydrophobic environment formed by these fatty acyl chains not only functions as a barrier between the inside and outside of the membrane, but also interacts with hydrophobic regions of membrane-bound proteins, which may affect the localization, stability, and function of membrane-bound proteins. For example, lipid rafts composed of sphingomyelin and cholesterol in the plasma membrane accumulate certain membrane proteins such as GPI-anchored proteins. We have found that dipalmitoylphosphatidylcholine (DPPC), whose phase transition temperature (42°C) is higher than body temperature, varies greatly in content from cell to cell, and that the function of a certain membrane receptor is greatly modified by the amount of DPPC. On the other hand, for example, phospholipids with highly unsaturated fatty acyl chains are abundant in the retina and play an important role in retinal function. We have generated a cell culture system deficient in highly unsaturated fatty acids and suggested the existence of a membrane-bound protein population requiring phospholipids with highly unsaturated fatty acid chains. As a result of advances in lipidome analysis and the elucidation of many lipid-metabolizing enzymes, we have reached a point where biomembrane fatty acid chains can be artificially regulated. Under these circumstances, it has become possible to comprehensively analyze the role of biomembrane fatty acid chains with respect to membrane-bound proteins.

In pharmacology textbooks, explanations are provided about the physiological activities of primarily five prostaglandins and thromboxane that are mainly produced through the activity of cyclooxygenase from the unsaturated fatty acid arachidonic acid, as well as the pharmacological actions of SAIDs and NSAIDs that inhibit their metabolism. With the advancement of omics technologies, it has become evident that not only these major lipid metabolites but also many other lipid metabolites dependent on various substrates and enzymes are produced and metabolized within the body. When comprehensively evaluating lipids produced and excreted in tissues and body fluids of diseased tissues or fluids, specific lipid production profiles reflecting each pathology are observed. These technologies can be applied as biomarkers and can also be used in the exploration of novel bioactive lipids. In our laboratory, we have utilized comprehensive concentration measurement techniques for bioactive lipids (lipidomics) to evaluate lipid profiles in tissues and body fluids of patients and animal models with allergic diseases such as food allergies, atopic dermatitis, and allergic rhinitis. Additionally, we have conducted explorations of the bioactivity of lipid metabolites produced therein. As a result, we have made discoveries related to biomarkers for food allergies and atopic dermatitis excreted in urine, as well as multiple lipids that exacerbate allergic inflammation. In this presentation, we would like to report these research findings.

Recently, oxidized phospholipids have been reported to be involved in various diseases. For example, lipid peroxides are involved in the induction of a new cell death form, "ferroptosis," and epoxidized ω3 fatty acids, an oxidized metabolite, are engaged in worsening allergies. Thus, although the importance of oxidized phospholipids is widely recognized in the induction of inflammation and cell death, the number of oxidized phospholipids available or detectable is limited. This lower number would be due to the lack of appropriate detection techniques.

Here, we have developed a fluorescent probe to detect "lipid-derived radicals," key molecules during the chain reaction of lipid peroxidation. Furthermore, since this probe can covalently bind to lipid-derived radicals, we have constructed an LC/FL/HRMS/MS system and have successfully analyzed the structures of 132 lipid-derived radical species. 　

Next, a non-targeted analysis of phosphatidylcholine-derived oxidized lipids (oxPCs) was performed using a high-resolution mass spectrometer, and a library of 465 oxPCs was constructed. Furthermore, we detected 70 kinds of oxPCs in mice with acetaminophen-induced acute liver failure, and mass imaging of oxidized lipids was successfully performed.

Furthermore, a novel screening system for oxidized lipid inhibition was developed. Notably, selecting compound had its inhibitory effect against retinal damages and bilateral common carotid artery occlusion model animals.

In this symposium, I would like to introduce our recent research and development status, including the detection and structural analysis of oxidized phospholipids and their application using animal models.

GTP-binding proteins (G proteins) are key intracellular signal mediators in response to extracellular physicochemical stimuli. The C-terminus of G proteins is a hypervariable region whose living structure is difficult to unravel, and we found that cysteine in this region has high redox activity and is involved in stress response and adaptation in the heart. We also revealed that the cysteine has a multiple sulfur atom-linked (supersulfide) residue (Cys -S_(n)SH, n≥1), which negatively regulates the functional activity of G proteins. Not only protein-bound supersulfides, but also intracellular inorganic supersulfides are highly nucleophilic and react positively with electrophilic lipid peroxides, which may act as an anti-oxidant and anti-cytotoxic agent. Furthermore, desupersulfidation of the mitochondria fission-accelerating G protein, dynamin-related protein 1, has been shown to promote the accumulation of lipid droplets in the liver due to high fat loading. In this symposium, we will also address the potential of sulfur-based lipid-redox interactions as a new therapeutic target.

In order to eliminate the bottleneck of non-clinical studies in infectious disease vaccine development research in Japan and to realize the 100-day mission, this study will bring together researchers in infectious disease vaccine research at Japan's top research institutions, the Institute of Medical Science of the University of Tokyo, the National Institute of Infectious Diseases, and the National Institute of Biomedical Innovation and Nutrition, to conduct GLP studies in small animals to primates, and to develop a new vaccine for infectious diseases. The three research institutes will collaborate with CROs capable of conducting GLP studies on small animals to primates, and under appropriate BSL management, will establish a research system that enables exploratory research and efficacy verification experiments for regulatory approval applications on novel coronaviruses, influenza viruses, and other unknown infectious pathogens, and will also develop a research system that will enable the development of young researchers. Promote seamless and borderless team building, including the development of young researchers.

Lab HP; https://vaccine-science.ims.u-tokyo.ac.jp/en/message/

U Tokyo Crowdfunding；https://utf.u-tokyo.ac.jp/project/pjt142

COVID-19 pandemic underscored the critical need for swift deployment of essential medical countermeasures, with vaccines playing a pivotal role. The successful development of vaccines hinges on the availability of a high-throughput platform that facilitates the rapid assessment of vaccine immunogenicity and reactogenicity. Given that these vaccine properties commonly originate from vaccine-elicited immune responses, it is imperative to gain a comprehensive understanding of vaccine immunity from multiple perspectives and at sufficient depths. In response to the challenges posed by the COVID-19 pandemic, cutting-edge technologies have been introduced to profile the immune system at both molecular and cellular levels. These advancements provide crucial insights into the dynamics of the immune system and identify molecular/cellular targets for innovative evaluation systems. This presentation highlights the potential of immune profiling, showing examples from COVID-19 and other vaccines to illustrate the impact and possibilities of these advancements.

In the mucosa, IgA antibodies are secreted as multimeric antibodies, which play important roles in normal flora control as well as in infection control. In contrast to IgG antibodies, which are predominantly specific for a single antigen, these mucosal IgA antibodies are known to be broadly antigen-specific, allowing a single type of antibody to respond to multiple antigens.

For SARS-CoV2, it has been shown that multimeric IgM and IgA antibodies can cope with more variants than IgG antibodies. Thus, the development of an effective mucosal vaccine adjuvant that induces mucosal polymeric IgA antibodies provides strong mucosal protection against bacterial and viral infections. This is very different from the conventional vaccine that stimulates the increase of antibody in the serum by intramuscular injection and targets the pathogen after invasion into the body. We believe that it is important for B cells activated by antigens to efficiently migrate to germinal centers in order to induce high-affinity antibodies on mucosal surfaces. We have therefore found a marker for pre-germinal center B cells and are conducting research on substances that induce this marker as novel mucosal vaccine adjuvants. We discuss the evaluation of mucosal immunity of vaccine adjuvants based on intestinal germinal center B cell responses.

By experiencing the COVID-19 pandemic, we researchers have learned a lot about infectious disease control. At a time when there is an urgent need to build a system to prepare for the next possible infectious disease pandemic, life science research is at a major turning point. Building a new research system to prepare for emerging and reemerging infectious diseases will depend on how quickly and smoothly we can switch research styles between normal and emergency situations and how efficiently we can gather the effort of researchers. The AMED BINDS project is the operation of a platform where groups of researchers with world-class technologies and facilities support life science researches and drug discovery in Japan during ordinary times. This network of BINDS researchers can also be a powerful aid in accelerating the development of vaccines and therapeutics in emergency situations. This presentation will introduce the ideal platform concept for emergency situations that would be possible with SCARDA and BINDS working together, as well as the actual good cooperation that has been achieved for M pox.

In the early 1990s, the amyloid cascade hypothesis was proposed based on genetic research into familial Alzheimer's disease (AD) as the mechanism of AD onset and progression. Subsequently, numerous clinical trials of agents based on this hypothesis were conducted, leading to many failures. However, these research results contributed to 1) the identification of toxic species, 2) the selection of the appropriate subject population, 3) the logical determination of dosages and administration durations based on biomarkers, and 4) the development of highly sensitive primary endpoints. This presentation provides an overview of the history of anti-Aβ drug development, non-clinical research on mechanisms of action, and clinical trial results, including biomarkers. It also outlines the prospects for future Alzheimer's disease drug development.

Disease-modifying anti-amyloid antibodies for Alzheimer's disease (AD) were approved in Japan this year and hold the promise of being included under healthcare coverage. The treatment of dementia is now at a major turning point.

Imaging technology for neurodegeneration has entered the era of proteinopathy imaging, starting with amyloid PET. Meanwhile, technological developments have made it possible to image tau lesions by tau PET, and prenatal diagnosis of tauopathy is improving dramatically.

In our cohort study, we performed amyloid and tau PET and compared changes in diagnosis, treatment, and management before and after PET. The results showed that the results of the two PETs changed the diagnosis of dementia by 35% and the treatment and management by 30%. (Shimohama S., 2022) In addition, we compared various blood biomarkers using highly reliable plasma samples obtained in the above study. As a result, we found that the HISCL amyloid-β42/40 ratio had high diagnostic accuracy (AUC:0.950). (Bun S., 2023) Furthermore, we were able to construct a predictive model of AD pathology with extremely high accuracy (AUC=0.994) based on comprehensive proteomics (3000 protein quantifications) using machine learning. This inexpensive and non-invasive blood biomarker can be a powerful tool for the upcoming introduction of dementia disease-modifying drugs.

In this talk, I will outline the prospects for AD disease-modifying drugs and the current status of protinopathy imaging and fluid biomarkers, and discuss the next-generation dementia treatment system.

The approval of Lecanemab, a monoclonal antibody that targets amyloid-β (Aβ) aggregates, marks a major milestone in drug discovery research for Alzheimer disease (AD). It confirms that Aβ is a key molecular driver of AD pathogenesis and a valid therapeutic target. However, it has also been shown that clearing Aβ aggregates from the brain does not fully stop the progression of AD. Therefore, new approaches are needed in addition to anti-Aβ antibodies. One promising avenue is targeting aggregated tau, another pathological hallmark of AD that is directly linked to neurodegeneration. Moreover, large-scale observational studies and clinical trials with anti-Aβ antibodies, as well as advances in biomarker development, have revealed the potential role of glial cells as a new target for drug discovery. Furthermore, drug discovery strategies for patients with advanced neurodegeneration are still lacking. In this presentation, I will summarize the current status and future challenges of AD drug discovery.

This presentation introduces efforts in predicting novel drug target genes using gene network analysis powered by Fugaku. While gene network analysis has traditionally been conducted, it has not sufficiently considered the variability in individual patients' responses to drugs and pathogens. Although AI-based methods are often evaluated solely on their predictive capabilities, this study expands on the concept of explainable AI using Bayesian networks. Leveraging Fugaku's computational power, we present an approach to explore novel drug candidate genes in a manner comprehensible to humans.

The demand for AI in drug discovery has been increasing, and various AI application prototypes have been developed to optimize the drug development process. However, unfortunately, these AI applications are not yet widely used in pharmaceutical companies' drug discovery efforts. One of the reasons for this is the decentralized nature of individual applications and the lack of an integrated platform. In the current state, researchers cannot easily utilize applications when needed.

To address this issue, we have incorporated approximately 20 AI and analytical technology applications we have developed into an integrated platform in a common computing infrastructure centered around the Supercomputer “Fugaku.” This platform is designed to construct workflows for drug target discovery, estimating target proteins. Specifically, we have incorporated information technologies like Graph Convolutional Networks and Bayesian Networks, which can predict candidate drug target molecules from large-scale biomedical data, including clinical data, omics data, and literature data. Ultimately, this platform allows the input of disease names, patient sample data, and more, enabling the estimation of disease mechanisms and target proteins using an HPC/AI workflow.

.In the early stage of drug development, high-throughput screening is carried out using experimental assays. It is currently estimated that there are over 10⁶³ potential compounds as drug candidates. Consequently, there has been growing interest in virtual drug screening as a cost-effective and time-efficient approach. Virtual screening methods can be divided into two types: an AI-based approach, which leverages machine learning models trained on existing experimental data, and a docking simulation, which is based on three-dimensional structures of target proteins. Whereas various techniques have been proposed in both approaches, a significant gap still exists in the virtual and real-world scenarios, such as imbalanced data and dynamics properties of molecules. In this presentation, we will introduce our efforts in practical evaluation of protein-compound evaluation in both the AI-based and the structure-based approaches. In the former, we have improved the model's generalizability with self-training method to address the lack of experimentally validated negative samples in the public databases. In the latter, we have successfully achieved molecular dynamics-based protein-drug screening by utilizing the supercomputer Fugaku. These achievements represent significant advances in next-generation computer-assisted drug discovery.

Epigenomes allow the rectification of disordered cancer gene expressions. This is the first study to illustrate patients’ molecular and cellular dynamics in response to an inhibitor designed for histone methyltransferase. We recently found the potency and mechanisms of action and resistance of an EZH1/2 dual inhibitor valemetostat in the clinical trials of patients with adult T-cell leukemia/lymphoma (ATL). Valemetostat administration reduced the tumor size and demonstrated durable clinical benefits. Integration of the intensive multilayered single-cell omics platform and clinical resources revealed that valemetostat abolished histone H3K27me3-mediated highly condensed chromatin and neutralized multiple gene loci, including tumor suppressor genes. Eliminating H3K27me3 led to reprogramming the cancer epigenome, thereby exerting a sustained benefit on tumors. Furthermore, both treatment-naive and treatment-adapted patients displayed the characteristic condensed chromatin structures, consistently suggesting that chromatin compaction is indispensable for tumor maintenance and growth. We hope that targeting the new concept “chromatin homeostasis” can provide a new avenue of vast opportunities for durable cancer treatment.

Mechanisms underpinning the dysfunctional immune response in SARS-CoV-2 infection are not yet fully understood. In addition, the functional roles of the genetic variants identified by COVID-19 genome-wide association study (GWAS) remain elusive, especially in non-European ancestry. We analyzed single-cell transcriptomes and T and B cell receptors of > 895,000 peripheral blood mononuclear cells from 73 COVID-19 patients and 75 healthy controls of Japanese ancestry with host genetic data. COVID-19 patients showed a low fraction of nonclassical monocytes (ncMono). We report downregulated cell transitions from classical monocytes to ncMono in COVID-19 with reduced CXCL10 expression in ncMono in severe disease. Cell-cell communication analysis inferred decreased cellular interactions involving ncMono in severe COVID-19, suggesting that the dysfunction of ncMono might be closely involved in the immunopathology of COVID-19 severity.  Clonal expansions of B cell receptors were evident in plasmablasts of patients. Putative disease genes identified by the GWAS of severe phenotypes showed cell type-specific expressions in monocytes and dendritic cells. A COVID-19-associated risk variant at the IFNAR2 locus (rs13050728) had COVID-19-specific and monocyte-specific expression quantitative trait loci effects, indicating the enrichment of host genetic risk in innate immune cells. Our multimodal and integrative single-cell analyses highlight biological and host genetic involvement of innate immune cells in COVID-19 severity.

Cardiovascular disease is a leading cause of death worldwide. Because adult cardiomyocytes (CMs) have a low regenerative capacity, damaged CMs are replaced by cardiac fibroblasts (CFs) after myocardial infarction (MI), leading to loss of contractile function of the heart and eventually to heart failure. There are no treatments available to regenerate myocardium and reverse fibrosis in MI. Direct cardiac reprogramming may be a promising approach for both cardiac regeneration and antifibrotic therapy. Overexpression of cardiac transcription factors, including Mef2c, Gata4, Tbx5, and Hand2 (MGTH), directly reprograms a subset of CFs into induced cardiomyocytes (iCMs) in vivo and vitro. Recently, we found that in vivo cardiac reprogramming generates new iCMs from resident CFs, improves cardiac function, and reduces fibrosis in chronic MI in mice. Single-cell RNA sequencing (scRNA-seq) demonstrated that in vivo cardiac reprogramming altered the interstitial cell landscape in chronic MI. In addition, scRNA-seq revealed that overexpression of MGTH in CFs not only induced iCMs, but also suppressed fibroblast gene signatures through the conversion of profibrotic CFs to a quiescent antifibrotic state. These findings suggest that in vivo cardiac reprogramming may become a pioneering therapy for chronic HF by regenerating cardiomyocytes and reducing fibrosis.

Cellular senescence is observed in various kinds of cells as a result of repeating proliferation or exposure to various genotoxic stresses. It is also known that senescent cells can accumulate in organs as aging and become a substrate of age-related disorders. A novel therapeutic strategy that eliminates senescent cells specifically from the body, so-called “lysis of senescent cells (senolysis)” has been demonstrated to ameliorate various age-related diseases and extend the lifespan of mammals without increasing cancer incidence. Our group has recently identified senescence-associated molecules through omics studies and developed “senolytic vaccine” targeting Glycoprotein nonmetastatic melanoma protein B (GPNMB) as an antigen upregulated in senescent endothelial cells. GPNMB-vaccine could exhibit senolysis leading to amelioration of atherosclerosis and diabetes as well as aged-phenotype in mice.

In our latest work, we have conducted single-cell analysis in senescent cells, which clarified the diversity of senescent cells and enabled more precise identification of senescence-associated molecules. The single-cell analysis-driven approach would be promising for understanding the nature of senescent cells as well as the efficient development of therapeutics targeting them.

As the brain has a high degree of functional specialization and is highlyintegrated at various hierarchies, it is necessary to investigate anatomical andfunctional brain networks unbiasedly and independently of any foreseenhypothesis to elucidate the pathophysiology of brain diseases. To address theissue, we have developed a highly scalable and high-speed imaging system(block-FAce Serial microscopy Tomography, FAST) and methods to comparestructures and neural activity among individual animal groups. Using thesemethods, we are examining anatomical structure and neuronal activity changes inanimal disease models and those administered with therapeutic drugs. In thissymposium, I will introduce our recent progress and discuss the directions offuture research that would contribute to a better understanding of brain systemsand disorders.

Addiction is defined as a psychic state of patients characterized by psychobehavioral changes such as compulsions to take a drug and reinforcing behaviors, even they know its side effects. It is difficult to prevent relapse of addiction in the present. In terms of drug dependence, it is urgent issue to investigate molecular and neurocircuit associated with drug-seeking behavior and therapeutic strategies. The formation of enduring associations between the primary rewarding properties of drugs and the environmental cues linked to drug use produces powerful triggers for relapse in abstinent addicts. The persistence of craving and high incidence of relapse following prolonged periods of abstinence in the addicted patient population is a major hurdle for therapeutic treatments. However, it remains unclear the molecular mechanism by which addictive drugs lead drug-seeking behaviors, due to the delay in technological development. We have recently developed novel comprehensive phosphoproteomic analysis and database that enables us to understand phosphorylation signal. In this symposium, I will discuss the signaling pathway in accumbal neurons using our phosphoproteomics in order to elucidate the molecular mechanism to induce drug-seeking behavior signal. I also propose the novel direction to treat addiction.

Microglia have a high capacity to repopulate in the adult brain. Microglial survival requires signaling via the colony-stimulating factor 1 receptor (CSF1R), and the removal/repopulation of microglia can be triggered by turning ON/OFF of CSF1R antagonists. Using this microglial replacement protocol ("reset"), we show its therapeutic effect on Alexander disease (AxD). AxD is a primary astrocytic disease caused by mutations in GFAP, but microglial activation occurs in the AxD brain as well. It is well known that many neurodegenerative and psychiatric diseases are accompanied by microglial activation, leading to neuroinflammation. Therefore, removal of microglia is considered one of the strategies for the treatment of these diseases. However, we found that microglial removal with CSF1R antagonists exersavated AxD pathology. This suggests that microglia, or at least some populations of them, play a beneficial role in AxD pathology. We found that reset, but not elimination of microglia ameliorated AxD pathology. Thus, we suggest that microglial replacement may be a better therapeutic strategy for AxD and possibly for other neurological diseases. We also report on the mechanisms underlying the therapeutic effect via microglial reset by RNAseq analysis.

We have performed a multi-scale synaptic analysis of mouse models of psychiatric disorders and found some candidate phenomena for the pathophysiology of the disorders. However, mouse models alone will not be sufficient to elucidate human psychiatric disorders. I believe that the combinatorial use of human-derived neurons, theoretical neuroscience and reverse translational feedback to mouse research is key. Human-derived samples include post-mortem brains, human iPSC-derived neurons and neurosurgically removed acute brain samples. While such human data can provide invaluable insights, they do not by themselves lead to an understanding of human disease. Therefore, to bridge the gap between the obtained "human data" and "our questions", we also use computational methods and integrate the human data into mathematical models, specifically the NEURON model, the Leaky Integrate-and-Fire model and the Free Energy model, and construct neuronal, circuit and behavioural models that implement the human parameters. In the talk I will present our current challenge of a rapid circulation between mouse, human and theoretical neuroscience to understand human psychiatric disorders.

Stress is a physical and mental strain caused by aversive and demanding conditions and risks mental illnesses, including depression and dementia. Rodent studies using stress models have shown that acute stress increases dendritic growth of prefrontal neurons and stress resilience via dopamine, whereas chronic stress activates microglia via the innate immune receptors TLR2/4, leading to neuronal and behavioral dysfunction. Chronic stress also promotes behavioral dysfunction by mobilizing leukocytes from the bone marrow. Thus, the role of inflammation in the brain and periphery in stress-induced neural dysfunction has been established. However, as our understanding of the biological basis of stress is still fragmentary, we and others are using single-cell omics and multi-omics analyses and molecular manipulations in a manner selective for brain regions and cell types to comprehensively identify the biological basis of stress-induced inflammation in the brain and periphery and link it to multiple behavioral domains. In this talk, I will present our recent findings on stress-induced inflammation and its relevance to neural dysfunction and discuss their implications for a cross-disease understanding of mental illnesses.

The central nervous system (CNS) hosts a variety of immune cells including two anatomically and transcriptionally distinct macrophage populations: microglia are found in the parenchyma, whereas CNS border-associated macrophages (CAMs) cover the CNS interfaces, such as the perivascular spaces and the meninges. Recent emergence of novel genetic tools and cutting-edge techniques including single-cell RNA-seq enables to study the CNS macrophages in more depth and have given novel insights into the origins, kinetics, functions, transcriptomic profiles, heterogeneity of microglia and CAMs. In this symposium, I will discuss our current knowledge of the characteristics of CNS macrophages.

In the brain, peripheral immune cells are localized in specific regions such as meningeal space, choroid plexus, and perivascular spaces, and contribute to brain development. Previous cohort studies have shown that meningeal inflammation during neonatal periods is a potent risk factor for neurodevelopmental disorders such as attention-deficit hyperactivity disorders (ADHD), however, the pathological mechanism underlying neonatal meningeal inflammation-induced neurodevelopmental disorders has been still unclear. To elucidate the pathological mechanism of neurodevelopmental disorders caused by neonatal meningeal inflammation, we induced meningeal inflammation in neonatal mice, and found that neonatal meningeal inflammation-induced mice exhibited ADHD-like behaviors in adulthood. Histological analysis and adeno-associated virus-based neurotracing or pharmacogenetics showed increased dopaminergic inputs in the nucleus accumbens (NAc) was responsible for ADHD-like behaviors. Moreover, a large number of inflammatory macrophages was observed in the brain after inducing meningeal inflammation, and macrophage depletion inhibited ADHD-like behaviors. These results demonstrated that ADHD-like behaviors after neonatal meningeal inflammation is caused by the formation of aberrant dopaminergic synapses in NAc by inflammatory macrophages.

Neuron-associated macrophages, shortly NAMs, are one of macrophage subsets which exists on peripheral neurons. NAMs have been identified in various organs including the intestine, skin, lung and adipose tissues. NAMs are responsible for maintaining the tissue integrity through protecting neurons and regulating the immune system. We also newly found out a NAM subset in the liver, especially on the portal vein. The portal vein is the most pivotal feeding vessel which transports food-derived nutrients from the gastrointestinal tract to the liver. Periportal NAM (pNAM) may be responsible for maintaining this vascular homeostasis and controlling the nutrient supply, however, the physiological functions remain uncovered. 

To reveal detailed molecular expressions of pNAM, we performed single-cell RNA sequencing and succeeded in identifying the pNAM cluster and its marker molecules. Estimation of physiological functions using differentially expressed genes in pNAM indicated a possibility that pNAM senses intravascular substances. To directly demonstrate this function, we established an intravital multiphoton imaging system for the portal vein. As the result, we successfully visualized uptake of intravascular substances by pNAM. We are currently investigating what happens in neurons after pNAM senses intravascular substances. Our final goal is to elucidate the importance of pNAM-neuron interactions in liver and portal vein function.

Nicotinamide adenine dinucleotide (NAD⁺) is an essential co-factor mediating numerous redox reactions. NAD⁺ is consumed as a substrate for poly(ADP-ribose) polymerase (PARP) and sirtuins and regulates various biological processes, such as metabolism, DNA repair, gene expression, and stress responses. In living organisms, the NAD⁺ levels are determined by a balance between NAD⁺ production and degradation. Recently, numbers of studies have demonstrated that NAD⁺ levels decline with age, and the deterioration of NAD⁺ metabolism promotes aging and aging-associated diseases, including metabolic diseases, neurodegenerative disease, and musculoskeletal diseases. Contrariwise, elevated NAD⁺ levels in tissue exhibit beneficial effects in both physiological and pathological aging. Various approaches, such as supplementation with NAD⁺ precursors, activation of NAD⁺ biosynthetic pathways, and inhibition of NAD⁺ degradation, have been used to increase NAD⁺ levels. In this presentation, I will show the recent progress regarding the role of NAD⁺ metabolism in aging and discuss the possibilities of NAD⁺ metabolism as a therapeutic target against aging