循環器病分子病態解析グループの研究内容

循環器疾患の発症や重症化には多くの遺伝要因と環境要因が関わっています。ゲノムなどのオミックス研究やiPS研究、疾患モデル研究などの基礎研究によって病態を解明したうえで、病態発症の分子機序を標的とした新規治療法の開発を目指します。

研究内容

現在の研究テーマ:
①遺伝性大動脈瘤の遺伝子解析と病態解明
②臓器透明化技術と多光子励起顕微鏡を用いた循環器疾患の三次元病理解析
③肺動脈性肺高血圧症の病態解明
④心筋細胞増殖の機序解明と制御法の開発

 

■遺伝性大動脈瘤・解離症の遺伝子解析と病態解明
 遺伝性大動脈瘤・解離症に対する遺伝学的検査を実施し、患者さんの臨床情報や手術検体などの試料を用いて、遺伝子型と表現型との関連性や遺伝子バリアントの機能解析、未知の原因遺伝子の探索、疾患モデルマウスを用いた病態解析研究などを行っています。
 マルファン症候群センター(マルファン外来)の詳細については、こちらをご覧ください。

■臓器透明化と多光子励起顕微鏡を用いた循環器疾患の三次元病理解析
 近年の臓器透明化技術の目覚しい発展により、臓器深層まで三次元かつ高解像度(一細胞解像度)で観察する画像解析技術の開発が期待されています。私たちは臓器透明化技術の一つであるCUBIC技術と多光子励起顕微鏡を用いて、心血管疾患の三次元構造や機能の変化(リモデリング)を評価するシステムの開発に取り組んでいます。

■肺動脈性肺高血圧症の病態解明
 肺動脈性肺高血圧症は、肺動脈圧の上昇とともに呼吸・循環不全が進行する希少難病ですが、発症・進展メカニズムの解明は十分ではありません。患者さんの遺伝背景を反映した疾患モデルマウスを作成し、一細胞解析や三次元病理解析システムを用いて、発症・進展に関わる分子基盤の解明を試みています。

■心筋細胞増殖の機序解明と制御法の開発
 近年、成体心筋細胞も僅かながらに自己再生(増殖)していることが報告されています。この内因性の心筋再生システムを増幅できれば、多くの患者さんに安全で効果的な治療を提供できるかもしれません。私たちは、この標的シグナルの一つであるHippo-YAP経路に着目し、ラット新生児心筋細胞やヒトiPS細胞由来心筋細胞の分裂・増殖を促進し、生体内でも極めて安定性が高い新規フッ素化化合物TT-10(C11H10FN3OS2)を創出しました。TT-10を用いた重症心不全治療の実現可能性について、多方面からの検討を行っています。

主要論文

Yagi H, Takeda N, Amiya E, Akiyama N, Chang H, Ishiura H, Sato J, Akazawa H, Morita H and Komuro I. Nonsyndromic arteriopathy and aortopathy and vascular Ehlers-Danlos syndrome causing COL3A1 variants. Am J Med Genet A. 2022;188:2777-2782.

Suzuki Y, Kaneko H, Yano Y, Okada A, Itoh H, Ueno K, Matsuoka S, Fujiu K, Michihata N, Jo T, Takeda N, Morita H, Yokota I, Node K, Yasunaga H and Komuro I. Dose-dependent relationship of blood pressure and glycemic status with risk of aortic dissection and aneurysm. Eur J Prev Cardiol. 2022.

Sayama S, Iriyama T, Takeda N, Yamauchi H, Toshimitsu M, Seyama T, Sone K, Kumasawa K, Nagamatsu T, Fujii T and Osuga Y. Proposed Management Policy for Pregnant Women with Loeys-Dietz Syndrome Following Prophylactic Aortic Root Replacement Based on Experience from a Tertiary Care Center. Int Heart J. 2022;63:176-179.

Goto K, Minatsuki S, Fujita K, Takeda N, Hatano M and Komuro I. Two Siblings With Peripheral Pulmonary Arterial Stenosis: Pulmonary Angiography of Advanced and Early Stages. Chest. 2022;161:e75-e80.

Taniguchi Y, Takeda N, Inuzuka R, Matsubayashi Y, Kato S, Doi T, Yagi H, Yamauchi H, Ando M, Oshima Y and Tanaka S. Impact of pathogenic FBN1 variant types on the development of severe scoliosis in patients with Marfan syndrome. J Med Genet. 2021.

Taniguchi Y, Matsubayashi Y, Kato S, Doi T, Takeda N, Yagi H, Inuzuka R, Oshima Y and Tanaka S. Predictive Physical Manifestations for Progression of Scoliosis in Marfan Syndrome. Spine (Phila Pa 1976). 2021;46:1020-1025.

Takeda N, Inuzuka R, Yagi H, Morita H, Ando M, Yamauchi H, Taniguchi Y, Porto KJ, Kanaya T, Ishiura H, Mitsui J, Tsuji S, Toda T, Ono M and Komuro I. Clinical Impact of Copy Number Variation on the Genetic Diagnosis of Syndromic Aortopathies. Circ Genom Precis Med. 2021;14:e003458.

Fujiwara T, Takeda N, Hara H, Ishii S, Numata G, Tokiwa H, Maemura S, Suzuki T, Takiguchi H, Kubota Y, Seo K, Sakata A, Nomura S, Hatano M, Ueda K, Harada M, Toko H, Takimoto E, Akazawa H, Nishimura S and Komuro I. Three-Dimensional Visualization of Hypoxia-Induced Pulmonary Vascular Remodeling in Mice. Circulation. 2021;144:1452-1455.

Hara H, Maemura S, Fujiwara T, Takeda N, Ishii S, Yagi H, Suzuki T, Harada M, Toko H, Kanaya T, Ijichi H, Moses HL, Takimoto E, Morita H, Akazawa H and Komuro I. Inhibition of transforming growth factor-beta signaling in myeloid cells ameliorates aortic aneurysmal formation in Marfan syndrome. PLoS One. 2020;15:e0239908.

Takeda N and Komuro I. Genetic basis of hereditary thoracic aortic aneurysms and dissections. J Cardiol. 2019;74:136-143.

Ito M, Hara H, Takeda N, Naito AT, Nomura S, Kondo M, Hata Y, Uchiyama M, Morita H and Komuro I. Characterization of a small molecule that promotes cell cycle activation of human induced pluripotent stem cell-derived cardiomyocytes. J Mol Cell Cardiol. 2019;128:90-95.

Fujiwara T, Takeda N, Ishii S, Morita H and Komuro I. Unique Mechanism by Which TGFBR1 Variants Cause 2 Distinct System Diseases- Loeys-Dietz Syndrome and Multiple Self-Healing Squamous Epithelioma. Circ Rep. 2019;1:487-492.

Takeda N, Inuzuka R, Maemura S, Morita H, Nawata K, Fujita D, Taniguchi Y, Yamauchi H, Yagi H, Kato M, Nishimura H, Hirata Y, Ikeda Y, Kumagai H, Amiya E, Hara H, Fujiwara T, Akazawa H, Suzuki JI, Imai Y, Nagai R, Takamoto S, Hirata Y, Ono M and Komuro I. Impact of Pathogenic FBN1 Variant Types on the Progression of Aortic Disease in Patients With Marfan Syndrome. Circ Genom Precis Med. 2018;11:e002058.

Takeda N, Hara H, Fujiwara T, Kanaya T, Maemura S and Komuro I. TGF-beta Signaling-Related Genes and Thoracic Aortic Aneurysms and Dissections. Int J Mol Sci. 2018;19.

Sayama S, Takeda N, Iriyama T, Inuzuka R, Maemura S, Fujita D, Yamauchi H, Nawata K, Bougaki M, Hyodo H, Shitara R, Nakayama T, Komatsu A, Nagamatsu T, Osuga Y and Fujii T. Peripartum type B aortic dissection in patients with Marfan syndrome who underwent aortic root replacement: a case series study. BJOG. 2018;125:487-493.

Hara H, Takeda N, Kondo M, Kubota M, Saito T, Maruyama J, Fujiwara T, Maemura S, Ito M, Naito AT, Harada M, Toko H, Nomura S, Kumagai H, Ikeda Y, Ueno H, Takimoto E, Akazawa H, Morita H, Aburatani H, Hata Y, Uchiyama M and Komuro I. Discovery of a Small Molecule to Increase Cardiomyocytes and Protect the Heart After Ischemic Injury. JACC Basic to translational science. 2018;3:639-653.

Fujiwara T, Takeda N, Hara H, Morita H, Kishihara J, Inuzuka R, Yagi H, Maemura S, Toko H, Harada M, Ikeda Y, Kumagai H, Nomura S, Takimoto E, Akazawa H, Ako J and Komuro I. Distinct variants affecting differential splicing of TGFBR1 exon 5 cause either Loeys-Dietz syndrome or multiple self-healing squamous epithelioma. Eur J Hum Genet. 2018;26:1151-1158.

Hara H, Takeda N and Komuro I. Pathophysiology and therapeutic potential of cardiac fibrosis. Inflamm Regen. 2017;37:13.

Takeda N, Yagi H, Hara H, Fujiwara T, Fujita D, Nawata K, Inuzuka R, Taniguchi Y, Harada M, Toko H, Akazawa H and Komuro I. Pathophysiology and Management of Cardiovascular Manifestations in Marfan and Loeys-Dietz Syndromes. Int Heart J. 2016;57:271-7.

Takeda N, Morita H, Fujita D, Inuzuka R, Taniguchi Y, Imai Y, Hirata Y and Komuro I. Congenital contractural arachnodactyly complicated with aortic dilatation and dissection: Case report and review of literature. Am J Med Genet A. 2015;167A:2382-7.

Li D, Takeda N, Jain R, Manderfield LJ, Liu F, Li L, Anderson SA and Epstein JA. Hopx distinguishes hippocampal from lateral ventricle neural stem cells. Stem Cell Res. 2015;15:522-529.

Jain R, Barkauskas CE, Takeda N, Bowie EJ, Aghajanian H, Wang Q, Padmanabhan A, Manderfield LJ, Gupta M, Li D, Li L, Trivedi CM, Hogan BLM and Epstein JA. Plasticity of Hopx(+) type I alveolar cells to regenerate type II cells in the lung. Nat Commun. 2015;6:6727.

Imai Y, Morita H, Takeda N, Miya F, Hyodo H, Fujita D, Tajima T, Tsunoda T, Nagai R, Kubo M and Komuro I. A deletion mutation in myosin heavy chain 11 causing familial thoracic aortic dissection in two Japanese pedigrees. Int J Cardiol. 2015;195:290-2.

Fujita D, Takeda N, Morita H, Kato M, Nishimura H, Inuzuka R, Taniguchi Y, Nawata K, Hyodo H, Imai Y, Hirata Y and Komuro I. A novel mutation of TGFBR2 causing Loeys-Dietz syndrome complicated with pregnancy-related fatal cervical arterial dissections. Int J Cardiol. 2015;201:288-90.

Fujita D, Takeda N, Imai Y, Inuzuka R, Komuro I and Hirata Y. Pathophysiology and Japanese clinical characteristics in Marfan syndrome. Pediatr Int. 2014;56:484-91.

Takeda N, Jain R, Li D, Li L, Lu MM and Epstein JA. Lgr5 Identifies Progenitor Cells Capable of Taste Bud Regeneration after Injury. PLoS One. 2013;8:e66314.

Takeda N, Jain R, Leboeuf MR, Padmanabhan A, Wang Q, Li L, Lu MM, Millar SE and Epstein JA. Hopx expression defines a subset of multipotent hair follicle stem cells and a progenitor population primed to give rise to K6+ niche cells. Development. 2013;140:1655-64.

Ogawa N, Imai Y, Nishimura H, Kato M, Takeda N, Nawata K, Taketani T, Morota T, Takamoto S, Nagai R and Hirata Y. Circulating transforming growth factor beta-1 level in Japanese patients with Marfan syndrome. Int Heart J. 2013;54:23-6.

Takeda N and Manabe I. Cellular Interplay between Cardiomyocytes and Nonmyocytes in Cardiac Remodeling. International journal of inflammation. 2011;2011:535241.

Takeda N, Jain R, LeBoeuf MR, Wang Q, Lu MM and Epstein JA. Interconversion between intestinal stem cell populations in distinct niches. Science. 2011;334:1420-4.

Ogawa N, Imai Y, Takahashi Y, Nawata K, Hara K, Nishimura H, Kato M, Takeda N, Kohro T, Morita H, Taketani T, Morota T, Yamazaki T, Goto J, Tsuji S, Takamoto S, Nagai R and Hirata Y. Evaluating Japanese patients with the Marfan syndrome using high-throughput microarray-based mutational analysis of fibrillin-1 gene. Am J Cardiol. 2011;108:1801-7.

Takeda N, Manabe I, Uchino Y, Eguchi K, Matsumoto S, Nishimura S, Shindo T, Sano M, Otsu K, Snider P, Conway SJ and Nagai R. Cardiac fibroblasts are essential for the adaptive response of the murine heart to pressure overload. J Clin Invest. 2010;120:254-65.

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