臨床薬学部門Department of Disease Control15図１図２ 線維化とは、組織にコラーゲン等の細胞外マトリックスが過剰に産生された状態である（図１）。切り傷などの組織損傷時には、損傷部は線維化によって補填され、やがてもとの実質細胞に置き換わる（創傷治癒）。一方で、この創傷治癒過程が破綻したり、慢性的な炎症が起こったりすると、組織においてコラーゲン等が過剰に沈着する。過剰な線維化は、組織を硬くすること等により、各種組織の機能を大きく低下させる。実際、線維化は、先進国の死因の約45%に関与すると報告されている。従って、線維化の制御は、高血圧時の心臓や肺線維症、慢性腎不全、脂肪肝さらには難治性癌等、患者数の多い、実に様々な病気において極めて重要な課題となっている（図２）。しかしながら、未だ決定的な線維化制御法は無く、線維化に対する画期的な治療法、治療薬の確立が望まれている。 組織の線維化は、コラーゲン等の細胞外マトリックスを産生する『筋線維芽細胞』という細胞群によって実行される。この筋線維芽細胞は組織が正常な時にはほとんど存在せず、炎症等によって、常在性の線維芽細胞など、様々な細胞が分化することにより生じる。しかしながら、筋線維芽細胞による線維化因子の過剰産生や分化に関するメカニズムは未だ多くの点が謎に包まれている。そこで我々は、筋線維芽細胞に着目し、様々な組織の線維化病態モデルを作成すること等により、筋線維芽細胞による線維化因子の過剰産生や分化に関与する新たな分子を探索している。そしてこの探索を通じて、線維化治療薬のための標的分子を同定し、革新的な線維化治療薬創生の分子基盤を構築したいと考えている。准教授 仲矢 道雄［博士（医学）］Associate Professor Michio Nakaya, Ph. D.分野連絡先分野連絡先 VGLL3 is a mechanosensitive protein that promotes cardiac fi brosis through liquid-liquid phase separation. Nat. Commun. 14, 550 (2023)#: equally contributed 2. Takanori Hironaka, Noburo Takizawa, Yuto Yamauchi, Yuma Horii, & Michio Nakaya The well-developed actin cytoskeleton and Cthrc1 expression by actin-binding protein drebrin in myofi broblasts promote cardiac and hepatic fi brosis. J. Biol. Chem. 299(3), 102934. (2023) 3. Yuma Horii#, Michio Nakaya*#, Hiroki Ohara#, Hiroaki Nishihara#, Kenji Watari, Akiomi Nagasaka, Takeo Nakaya, Yuki Sugiura, Toshiaki Okuno, Tomoaki Koga, Akira Tanaka, Takehiko Yokomizo & Hitoshi Kurose Leukotriene B4 receptor 1 exacerbates infl ammation following myocardial infarction. FASEB J. 34(6), 8749-8763. (2020) *: corresponding author #: equally contributed 4. Michio Nakaya*, Kenji Watari, Mitsuru Tajima, Takeo Nakaya, Shoichi Matsuda, Hiroki Ohara, Hiroaki Nishihara, Hiroshi Yamaguchi, Akiko Hashimoto, Mitsuho Nishida, Akiomi Nagasaka, Yuma Horii, Hiroki Ono,Gentaro Iribe, Ryuji Inoue, Makoto Tsuda, Kazuhide Inoue, Akira Tanaka, Masahiko Kuroda, Shigekazu Nagata, & Hitoshi Kurose Cardiac myofibroblast engulfment of dead cells facilitates recovery after myocardial infarction. J. Clin. Invest. 127, 383-401(2017) *: corresponding author 5. Michio Nakaya, Mitsuru Tajima, Hidetaka Kosako, Takeo Nakaya, Akiko Hashimoto, Kenji Watari, Hiroaki Nishihara, Mina Ohba, Shiori Komiya, Naoki Tani, Motohiro Nishida, Hisaaki Taniguchi, Yoji Sato, Mitsuru Matsumoto, Makoto Tsuda, Masahiko Kuroda, Kazuhide Inoue & Hitoshi Kurose GRK6 defi ciency in mice causes autoimmune disease due to impaired apoptotic cell clearance. Nat. Commun. 4, 1532 (2013)[Research]Fibrosis is characterized by excessive accumulation of extracellular matrix proteins such as collagen in tissues (Fig. 1). In the tissue injury, such as a cut, the injured area is filled with extracellular matrix proteins and is eventually replaced by the original parenchymal cells (wound healing). On the other hand, when the wound healing process is disrupted or chronic inflammation occurs, extracellular matrix proteins are excessively deposited in the tissues. Excessive fibrosis can severely impair the function of various tissues by hardening the tissues. In fact, fibrosis has been reported to be responsible for approximately 45% of deaths in developed countries. Therefore, the control of fibrosis is an extremely important issue in various diseases with a large number of patients, such as cardiac fibrosis in hypertension, idiopathic pulmonary fibrosis, chronic renal failure, fatty liver, and intractable cancer (Fig. 2). However, there are no definitive methods for fibrosis control so far, and a breakthrough therapy and drug for fibrosis is necessary.Tissue fibrosis is caused by a group of myofibroblasts that produce extracellular matrix components such as collagen. Myofibroblasts do not exist in normal tissues; however, various cells are known to differentiate into myofibroblasts upon inflammation. However, the mechanisms involved in the overproduction and differentiation of fibrotic factors by myofibroblasts remain largely unknown. Therefore, we are searching for new molecules involved in the overproduction and differentiation of fibrotic factors by myofibroblasts by creating models of fibrosis pathology in various tissues, focusing on myofibroblasts. Through this search, we hope to identify target molecules for anti-fibrosis drugs and build a molecular basis for the creation of innovative anti-fibrosis drugs. 【代表論文】1. Yuma Horii#, Shoichi Matsuda#, ChikashiToyota, Takumi Morinaga, Takeo Nakaya, Soken Tsuchiya, Masaki Ohmuraya, Takanori Hironaka, Ryo Yoshiki, Kotaro Kasai, Yuto Yamauchi, Noburo Takizawa, Akiomi Nagasaka, Akira Tanaka, Hidetaka Kosako, & Michio Nakaya 仲矢 道雄（Michio Nakaya）仲矢 道雄（Michio Nakaya）TEL&FAX: 092-642-6878E-mail : nakaya@phar.kyushu-u.ac.jpURL : https://chudoku.phar.kyushu-u.ac.jp准教授仲矢 道雄Associate Prof. Nakaya線維芽細胞実質細胞特発性特発性肺線維症肺線維症筋線維芽細胞細胞外マトリックスウイルス性肝炎ウイルス性肝炎非アルコール性非アルコール性脂肪性肝炎脂肪性肝炎心筋■塞心筋■塞高血圧性高血圧性心肥大心肥大心臓心臓肺肺正常時の臓器各臓器の機能低下肝臓肝臓線維化時の臓器慢性腎不全慢性腎不全（糖尿病性腎症（糖尿病性腎症など）など）腎臓腎臓線維化疾患制御学分野
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