Research Themes

• 癌細胞由来分泌型FLRT2を介した口腔癌の浸潤・遠隔転移様式の解明
  Apr. 2023 - Mar. 2026
• Identification of a possible molecular mechanism causing an idiopathic osteolysis Gorham Stout disease
  Grant-in-Aid for Scientific Research (C)
  Tokyo Medical and Dental University
  01 Apr. 2022 - 31 Mar. 2025
• 細胞骨格制御を基盤とした溶骨症治療の新戦略　　　　　　　　　　　　　　　
  Apr. 2019 - Mar. 2022
• 筋骨格系の異所性骨化症の発症分子機構の解明と治療法開発　　　　　　　　　　　　　　　
  2016 - 2018
• 骨粗鬆症の病態制御へのIRISINと協調する新分子機構とエピジェネティクスの解明　　　　　　　　　　　　　　　
  2016 - 2017
• 骨形成の統合的メカニカルシグナル制御ネットワークの新分子機構　　　　　　　　　　　　　　　
  2014 - 2017
• 組織再生医療に用いられる間葉系幹細胞の品質保証評価に有効な遺伝子発現の解析　　　　　　　　　　　　　　　
  2013 - 2015
• Epigenetics of mesenchymal stem cells considering regenerative therapy for osteoarthritis
  Grant-in-Aid for Scientific Research (C)
  Tokyo Medical and Dental University
  2010 - 2012
  The differentiating potentials of human mesenchymal stem cells (hMSCs) were analyzed from epigenetic aspect. By analyzing cytosine methylation status of various gene loci, an upstream region of stromal derived factor 1 (also called as CSCL12) gene was hypothesized to function as silencer element of this gene in hMSCs. Although the alteration of cytosine methylation was a rare event in the in vitro differentiation system, global analysis indicated consistent differences could be represented among hMSCs with different tissue origins, which may reflect relatively long term epigenetic history of individual cells.
• Elucidation of roles of Dullard, a BMP signal inhibitor in bone formation
  Grant-in-Aid for Young Scientists (B)
  Tokyo Medical and Dental University
  2009 - 2010
  Bone morphogenetic protein (BMP) plays crucial roles in skeletal formation, and its signal level is regulated properly by negative regulators. In the present study, I investigated involvement of novel BMP inhibitor Dullard in bone formation. I found that Dullard is localized in intracellular membrane structure, expressed in osteoblast, and suppress BMP signaling at least at intracellular signal transducer Smad1 level.
• Molecular Analyses of Osteoblastic Niche and its Application with the Development of Nano Science
  Grant-in-Aid for Scientific Research (S)
  Tokyo Medical and Dental University
  2006 - 2010
  To understand the mechanism of boneformation factors that are involved in the regulation and pathology, we have been examining molecular bases with respect to the micro environment. We identified that and CIZ is involved in the regulations ob bone information by altering the signaling of osteoblasts. CIZ and ECM proteins are regulating cell attachment and transcription. BMP is a most critical cytokine for bone information and implicated in niche regulation. Niche for bone cells and the regulation of cells in such location has not been well elucidated. As interaction of local and systemic hormone is important for coordinate regulation of bone formation we focused on parathyroid hormone (PTH). Such systemic hormonal control exerts its effect through the regulation of local target tissues, which in turn regulate upstream signals in a feedback loop. Parathyroid hormone receptor (PPR) transgenic mice expressing a constitutively active form of the receptor (caPPR) specifically in cells of the osteoblast lineage have a high bone mass phenotype. In these mice, OPN deficiency further increased bone mass. Bone formation was also found to be controlled by ANA and Cnot7 that inhibit BMP. Epigentic link and PTH dependent regulation by M-CSF and MCP is also found to be important. Regeneration of bone requires the combination of appropriate drugs and an appropriate delivery system to control cell behavior. However, the delivery of multiple drugs to heal bone is complicated by the availability of carriers. The aim of this study was to explore a new system for delivery of a selective EP4 receptor agonist (EP4A) in combination with low-dose bone morphogenetic protein 2 (BMP-2). Combination treatment with EP4A and low-dose BMP-2 in nanogel efficiently activated bone cells to regenerate calvarial bone by forming both outer and inner cortical plates as well as bone marrow tissue to regenerate a structure similar to that of intact calvaria. EP4A enhanced low-dose BMP-2-induced cell differentiation and activation of transcription events in osteoblasts. These data indicate that combined delivery of EP4A and low-dose BMP-2 via nanogel-based hydrogel provides a new system for bone repair.
• 悪性黒色腫の骨の転移のメカニズムの解明
  2008 - 2009
• Analysis of DNA methylation in the mesenchymal stem cells differentiating into bone and cartilage cells
  Grant-in-Aid for Scientific Research (C)
  Tokyo Medical and Dental University
  2007 - 2008
• 非コラーゲン性骨基質蛋白オステオポンチンの細胞制御メカニズム
  2006 - 2007
• 蛋白ユビキチンリガーゼMurf1による骨と筋肉の廃用性萎縮における連関機構の解析
  2006 - 2006
• 四肢の発生における骨・軟骨制御因子の役割の解明
  2004 - 2005
• Systematic analysis of polymorphisms and linkage dsequilibrium in the osteoporosis susceptibility genes
  Grant-in-Aid for Scientific Research (B)
  2003 - 2004
  To clarify the genomic linkage of polymorphisms in the candidate gene loci of osteoporosis susceptibility genes, 12 candidate gene loci were selected through our original investigation of large scale single nucleotide polymorphism (SNP) association study using thousands of population subjects. By extracting multiple useful SNPs distributing throughout and beyond the loci in some cases, we analyzed linkage disequilibrium (LD) of those loci. Analyzed loci were the vitamin D binding protein gene (DBP), interleukin-1 receptor associated kinase 1 gene (IRAK1), tumor necrosis factor receptor-associated factor interacting protein gene (I-TRAF), gonadotropin releasing hormone gene (GnRH), glutaminyl-peptide cyclotransferase (QPCT), low density lipoprotein receptor-related protein 5 gene (LRP5), proopiomelanocortin gene (POMC), leukemia inhibitory factor receptor gene (LIFR), adducin 1 gene (ADD1), bone morphogenetic protein 8 gene (BMP8), heat shock protein 1A gene (HSPAIA), and the osteoclast-associated receptor gene (OSCAR). Analyses on some regions was difficult because of the existence of neighboring duplicated genes, like BMP8, however long range PCR usually solved the problem. By analyzing the indices of LD, D' and r2, we generally detected a single LD block covering the entire locus in each gene, however in several gene loci like LRP5 locus multiple block was observed. By clarifying the extent and the degree of LD in those loci, and selecting representative tag-SNPs in each LD blocks, we continued the association study using larger subject groups, to understand the genetic contribution of these candidate gene polymorphisms for bone mass determination.