Sakura Small

 

准教授 Ph. D 中村 能久
助教 Ph. D 谷貝 知樹



炎症は外傷や感染に対する重要な生体防御反応の一つです。一方、老化や肥満により、炎症反応の制御が不全、もしくは破綻し、慢性炎症や組織障害を伴う病態へと発展します。また、老化や肥満に伴う異常な炎症反応は、脳やエネルギー代謝組織などにおいて誘導されるインスリン抵抗性の分子基盤であり、2型糖尿病や非アルコール性脂肪肝炎、動脈硬化などの慢性炎症性疾患の発症の一因と考えられています。老化や肥満に起因する病態の患者が急増している現在、慢性炎症の発症機構の解明は急務になっています。

私たちは、この課題に対し、主に3つのアプローチにより迫っています:

  1. 炎症性反応に関わる二重鎖RNA結合タンパク質に焦点を絞り、内在性二重鎖RNAの動的変化を解析する。
  2. エキソソームなどの細胞外小胞によって運ばれるRNAを介したインスリン抵抗性の惹起と炎症性反応の誘導機構を解析する。
  3. 肝臓のmiRNAネットワクークによる代謝と炎症反応の制御機構を解析する。

これらのアプローチにより、細胞内・外のRNAネットワークの変化に注目し、2型糖尿病や肝炎、動脈硬化といった疾患の共通点を体系的に捉えることを目的にしています。この研究により、慢性炎症を基盤とする病態の共通点見出し、新しい創薬・治療戦略を立てることを目指しています。

Published Study:
Peer reviewed articles
Kim A, Shah A, Nakamura T. “Extracellular Vesicles: A potential novel regulator of obesity and its associated complications.” Children. 2018 Nov 15;5(11), PubMed ID: 30445758.

Salem ESB, Murakami K, Takahashi T, Bernhard E, Borra, V, Bethi M, Nakamura T*. “Isolation of Primary Mouse Hepatocytes for Nascent Protein Synthesis Analysis by Non-Radioactive L-Azidohomoalanine Labeling Method.” Journal of Visualized Experiments. 2018 Oct 23; 140. PubMed ID: 30417869.

Zhang C, Seo J, Murakami K, Salem ESB, Bernhard E, Borra V, Choi K, Yuan CL, Chan C, Chen X, Huang T, Weirauch MT, Divanovic S, Qi NR, Thomas HE, Mercer CA, Siomi H, Nakamura T*. “Hepatic Ago2-mediated RNA silencing controls energy metabolism linked to AMPK activation and obesity-associated pathophysiology.” Nature Communications. 2018 Sep 10; 9(1): 3658, PubMed ID: 30201950.

Peng J, Li Y, Deng S, Holland J, Yates E, Chen J, Gu H, Wang X, Essandoh K, Mu X, McNamara RK, Peng T, Jegga AG, Nakamura T*, Huang K*, Perez-Tilve D*, Fan G*. “An Hsp20-FBXO4 Axis Regulates Adipocyte Function through Modulating PPARγ Ubiquitination.” Cell Reports. 2018 June 19; 23(12):3607-3620, PubMed ID: 29925002.

Yamazaki T, Li W, Yang L, Li P, Cao H, Motegi SI, Udey MC, Bernhard E, Nakamura T, Mukouyama YS. “Whole-mount adult ear skin imaging reveals defective neuro-vascular branching morphogenesis in obese and type 2 diabetic mouse models” Sci Rep. 2018 Jan 11;8(1):430, PubMed ID: 29323138.

Zhang C, Seo J, Nakamura T*. “Cellular approaches in investigating Argonaute 2-dependent RNA silencing.” Methods Mol Biol. 2018 1680: 205-215, PubMed ID: 29030851. *

Youssef OA, Safran SA, Nakamura T, Nix DA, Hotamisligil GS, Bass BL. “A potential role for snoRNAs in PKR activation during metabolic stress.” Proc Natl Acad Sci U S A. 2015 Apr; 112 (16): 5023-5028, PubMed ID: 25848059.

Nakamura T*, Kunz RC, Zhang C, Kimura T, Yuan CL, Baccaro B, Namiki, Y, Gygi SP, Hotamisligil GS*. “A critical role of PKR complexes with TRBP in immunometabolic regulation and eIF2alpha phosphorylation in obesity.” Cell Reports. 2015 Apr 14;11(2):295-307, PubMed ID: 25843719.

Nakamura T, Arduini A, Baccaro B, Furuhashi M, Hotamisligil GS. “Small molecule inhibitors of PKR improve glucose homeostasis in obese, diabetic mice.” Diabetes. 2014 Feb; 63 (2): 526-534, PubMed ID: 24150608.

Lu B, Nakamura T, Inouye K, Valdes-Ferrer SI, Olofsson PS, Li J, Wang H, Erlandsson-Harris, Andersson U, Yang H, Chavan SS, Hotamisligil GS, Tracey KJ. “PKR is required for NLRP3 inflammasome activation and HMGB1 release.” Nature. 2012 Aug 30; 488 (7413): 670-4, PubMed ID: 22801494.

Morita M. Oike Y, Nagashima T, Kadomatsu T, Tabata M, Suzuki T, Nakamura T, Yoshida N, Okada M, Yamamoto T. “Obesity resistance and increased hepatic expression of catabolism-related mRNAs in Cnot3(+/-) mice.” EMBO J. 2011 Sep 6; 30 (22): 4678-4691, PubMed ID: 21897366.

Nakamura T, Furuhashi M, Li P, Cao H, Tuncman G, Sonenberg N, Gorgun CZ, Hotamisligil GS. “Double-stranded RNA-dependent Protein Kinase Links Pathogen Sensing with Stress and Metabolic Homeostasis.” Cell. 2010 Feb 5; 140 (3): 338-348, PubMed ID: 20144759.

Murohashi M, Nakamura T, Tanaka S, Ichise T, Yoshida N, Yamamoto T, Shibuya M, Schlessinger J, Gotoh N. “An FGF-FRS2alpha-Cdx2 Axis in Trophoblast Stem Cells Induces Bmp4 to Regulate Proper Growth of Early Mouse Embryos.” Stem Cells. 2009 Nov 3; 28 (1): 113-121, PubMed ID: 19890878.

Horiuchi M, Takeuchi K, Noda N, Muroya N, Suzuki T, Nakamura T, Kawamura-Tsuzuku J, Takahasi K, Yamamoto T, Inagaki F. “Structural basis for the antiproliferative activity of the Tob-hCaf1 complex.” J Biol Chem. 2009 May 8; 284 (19): 13244-13255, PubMed ID: 19276069.

Yoneda M, Suzuki T, Nakamura T, Ajima R, Yoshida Y, Kakuta S, Sudo K, Iwakura Y, Shibutani M, Mitsumori K, Yokota J, Yamamoto T. “Deficiency of antiproliferative family protein Ana correlates with development of lung adenocarcinoma.” Cancer Science. 2009 Feb; 100 (2): 225-232, PubMed ID: 19068083.

Hirata T, Amiya S, Akiya M, Takei O, Sakai T, Nakamura T, Tsuzuku JK, Yamamoto T, Hatakeyama R. “Chemical Modification of Carbon Nanotube Based Bio-Nanosensor by Plasma Activation.” Jpn J Applied Physics. 2008 Apr 18; 47 (4): 2068-2071, Accession Number: WOS:000255449000033.

Ajima R, Akiyama T, Usui M, Yoneda M, Yoshida Y, Nakamura T, Minowa O, Noda M, Tanaka S, Noda T, Yamamoto T. “Osteoporotic bone formation in mice lacking tob2; involvement of Tob2 in RANK ligand expression and osteoclasts differentiation.” FEBS Lett. 2008 Apr 16; 582 (9): 1313-8, PubMed ID: 18358842.

Morita M, Suzuki T, Nakamura T, Yokoyama K, Miyasaka T, Yamamoto T. “Depletion of mammalian CCR4b deadenylase triggers elevation of the p27Kip1 mRNA level and impairs cell growth.” Mol Cell Biol. 2007 Jul; 27 (13): 4980-90, PubMed ID: 17452450.

Washio-Oikawa K, Nakamura T, Usui M, Yoneda M, Ezura Y, Ishikawa I, Nakashima K, Noda T, Yamamoto T, Noda M. “Cnot7-null mice exhibit high bone mass phenotype and modulation of BMP actions.” J Bone Miner Res. 2007 Aug; 22 (8): 1217-23, PubMed ID: 17451368.

Kawa S, Ito C, Toyama Y, Maekawa M, Tezuka T, Nakamura T, Nakazawa T, Yokoyama K, Yoshida N, Toshimori K, Yamamoto T. “Azoospermia in mice with targeted disruption of the Brek/Lmtk2 (brain-enriched kinase/lemur tyrosine kinase 2) gene.” Proc Natl Acad Sci U S A. 2006 Dec 19; 103 (51): 19344-9, PubMed ID: 17158803.

Washio-Oikawa K, Nakamura T, Usui M, Yoneda M, Ezura Y, Ishikawa I, Nakashima K, Yamamoto T, Noda M. “Expression analysis of LacZ gene placed in the locus of Cnot7 exhibits its activity in osteoblasts in vivo and in mineralized nodules in vitro.” J Cell Biochem. 2006 Oct 1; 99 (2): 538-44, PubMed ID: 16639713.

Ogawa T, Ito C, Nakamura T, Tamura Y, Yamamoto T, Noda T, Kubota Y, Toshimori K. “Abnormal sperm morphology caused by defects in Sertoli cells of Cnot7 knockout mice.” Arch Histol Cytol. 2004 Nov; 67 (4): 307-14, PubMed ID: 15700538.

Nakamura T, Yao R, Ogawa T, Suzuki T, Ito C, Tsunekawa N, Inoue K, Ajima R, Miyasaka T, Yoshida Y, Ogura A, Toshimori K, Noce T, Yamamoto T, Noda T. “Oligo-astheno- teratozoospermia in mice lacking Cnot7, a regulator of retinoid X receptor beta.” Nat Genet. 2004 May; 36 (5): 528-33, PubMed ID: 15107851.

Goto J, Tezuka T, Nakazawa T, Tsukamoto N, Nakamura T, Ajima R, Yokoyama K, Ohta T, Ohki M, Yamamoto T. “Altered gene expression in the adult brain of fyn-deficient mice.” Cell Mol Neurobiol. 2004 Feb; 24 (1): 149-59, PubMed ID: 15049519.

Kimura H*, Nakamura T*, Ogawa T, Tanaka S, Shiota K. “Transcription of mouse DNA methyltransferase 1 (Dnmt1) is regulated by both E2F-Rb-HDAC-dependent and -independent pathways.” Nucleic Acids Res, 2003 Jun 15; 31 (12): 3101-13, PubMed ID: 12799438. *These authors contributed equally to this work.

Yoshida Y*, Nakamura T*, Komoda M, Satoh H, Suzuki T, Tsuzuku JK, Miyasaka T, Yoshida EH, Umemori H, Kunisaki RK, Tani K, Ishii S, Mori S, Suganuma M, Noda T, Yamamoto T. “Mice lacking a transcriptional corepressor Tob are predisposed to cancer.” Genes Dev. 2003 May 15; 17 (10): 1201-6, PubMed ID: 12756225. *These authors contributed equally to this work.

Suzuki T, K-Tsuzuku J, Ajima R, Nakamura T, Yoshida Y, Yamamoto T. “Phosphorylation of three regulatory serines of Tob by Erk1 and Erk2 is required for Ras-mediated cell proliferation and transformation.” Genes Dev. 2002 Jun 1; 16 (11): 1356-70, PubMed ID: 12050114.

Yoshida Y, Hosoda E, Nakamura T, Yamamoto T. “Association of ANA, a member of the antiproliferative Tob family proteins, with a Caf1 component of the CCR4 transcriptional regulatory complex.” Jpn J Cancer Res. 2001 Jun; 92 (6): 592-6, PubMed ID: 11429045.

 
Non-peer reviewed articles (Book chapter/Review/Commentary)
Nakamura T. “Role of double-stranded RNA pathways in Immunometabolism in Obesity.” Springer: Chronic Inflammation – Mechanisms and Regulation. 2016; 277-290, ISBN: 978- 4-431-56068-5 (Review).

Nakamura T. “The Role of dsRNA pathways in inflammation and cancer in obesity” Journal of Clinical and Experimental Medicine. 2016 Jun; 257 (12): 1245-1250 (Review in Japanese).

Nakamura T. “dsRNA in immunometabolism” Oncotarget. 2015 Aug; 6 (24): 19940-19941, PubMed ID: 26343371 (Review).

Nakamura T. “Molecular mechanism of double-stranded RNA pathway-mediated immunometabolic regulation” BIO Clinica: Lipid metabolism and signaling. 2015 Aug; 30 (9): 838-842 (Review in Japanese).

Nakamura T. “Role of double-stranded RNA pathways in immune-metabolic regulation” BIO Clinica Special Edition: Chronic inflammation in endocrinology and metabolism. 2015 Feb; 4 (1): 104-108 (Review in Japanese).

Nakamura T. “Molecular basis of chronic inflammatory responses and metabolic diseases in obesity” Experimental Medicine. 2014 Feb; 32 (3): 380-385 (Review in Japanese).

Nakamura T. “Revisiting Metformin” Science Translation Medicine. 5 (172), p172ec31, 2013 (Commentary).

Nakamura T. “Microbes and Type 1 Diabetes” Science Translation Medicine. 5 (168), p168ec14, 2013 (Commentary).

Nakamura T. “Resveratrol: Too Early to Bring Out the Wine?” Science Translation Medicine. 4 (164), p164ec228, 2012 (Commentary).

Nakamura T. “Weighty Considerations” Science Translation Medicine. 4 (160), p160ec209, 2012 (Commentary).

Nakamura T. “A Warning Bell Tolls for Type 1 Diabetes” Science Translation Medicine. 4 (156), p156ec189, 2012 (Commentary).

Nakamura T. “Microbial Manipulation of Metabolism” Science Translation Medicine. 4 (148), p148ec153, 2012 (Commentary).

Nakamura T. “Mitochondrial Workout” Science Translation Medicine. 4 (144), p144ec134, 2012 (Commentary).

Nakamura T. “You Are What and When You Eat” Science Translation Medicine. 4 (141), p141ec116, 2012 (Commentary).

Nakamura T. “Perceiving Your Appetite” Science Translation Medicine. 4 (136), p136ec97, 2012 (Commentary).

Nakamura T. “Bypassing Alzheimer’s Diseases” Science Translation Medicine. 4 (132), p132ec79, 2012 (Commentary).

Nakamura T. “Bypassing Alzheimer’s Diseases” Science Translation Medicine. 4 (132), p132ec79, 2012 (Commentary).

Nakamura T. “Diseases of Resistance” Science Translation Medicine. 4 (128), p128ec60, 2012 (Commentary).

Nakamura T. “What’s Up with BAT?” Science Translation Medicine. 4 (125), p125ec45, 2012 (Commentary).

Nakamura T and Hotamisligil GS. “Impact of qualitative alterations of lipid on metabolism in obesity” Experimental Medicine. 2012 Feb; 30 (3): 435-440 (Review in Japanese)

Nakamura T and Hotamisligil GS. “Obesity, ER stress, and metabolic disease” Experimental Medicine. 2009 Mar; 27 (4): 498-504 (Review in Japanese).