国立研究開発法人 国立成育医療研究センター National Center for Child Health and Development

代表: 03-3416-0181 / 予約センター(病院): 03-5494-7300
〈月~金曜日(祝祭日を除く)9時〜17時〉

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研究者・企業の方へ Scholar & Enterprise

研究者・企業の方へ Scholar & Enterprise

システム発生・再生医学研究部

研究部紹介

遺伝子発現データベースの構築や新規の研究システムの開発、ゲノム情報を利用した解析により、個体発生や細胞分化、組織が構成される際のメカニズムを分子レベルで明らかにし、成育疾患の原因解明へと応用していきます。また、研究成果をもとに疾患モデルマウスを開発していきます。
これまでの研究で、遺伝子が、必要な時期に必要な量を発現しなかった場合に発症する疾患が多数報告されています。正常な胎児の発生や、小児の発育に必要な遺伝子の発現状態と機能を明らかにすることは、成育疾患の原因究明には必要不可欠です。
当部は遺伝子発現の正常な状態を明らかにするとともに、その状態の破綻としての病態の解明を目指します。胎児での解析が可能なマウスをモデルとして用いて、発生学、遺伝学、ゲノム生物学、分子生物学、発生工学に基づいた手法により研究を進めています。現在は主に生殖腺形成(性決定、性分化)、エピジェネティクス、マイクロRNA、ゲノム編集技術について研究しています。


研究内容

  1. 新規の遺伝子発現データベースの構築
    胎児の組織が形作られるときの分子メカニズムを理解することは、組織の形成不全や胎児期に由来する成育疾患を理解するために必要不可欠です。そのため、各組織を形作るのに必要な遺伝子の同定を目指して新規遺伝子発現データベースを作製しています。
  2. ハイスループット遺伝子発現解析
    胎児の各組織で特異的に発現する遺伝子の発現制御のメカニズムを明らかにするため、多数の遺伝子を細胞に一つずつ強制発現させ、各遺伝子の機能の解析を行っています。この解析のための手法を自動化することにより、ハイスループットな研究が可能になっています。
  3. ゲノム科学からの成育疾患の原因解明
    ゲノム配列の中で機能が分かっている部分は一部に過ぎません。機能が不明なゲノムの領域に存在し、成育疾患に関与する配列の同定とゲノムの機能の解析を行っています。この研究により、これまで原因が分からなかった成育疾患の原因の同定や、病態解明を目指しています。
  4. 迅速遺伝子破壊マウス作製法による疾患モデルマウスの作製
    近年開発されたゲノム編集法を応用することにより、短時間に遺伝子破壊マウスを作製し、多数の疾患モデルマウスを作ることを目指しています。また、ゲノム編集法を応用した研究手法の開発やさらに高効率な遺伝子破壊マウスの作製法の開発も行っています。
  5. 次世代シークエンサを用いた変異解析
    バイオインフォマティクスを駆使した変異解析を行い、成育疾患の原因探索、また再生医学に用いられる細胞の変異検出等を行っています。

○研究部問い合わせ窓口

高田 修治
高田修治のメールアドレスの画像

スタッフ

システム発生・再生医学研究部

組織工学研究室

ゲノム機能研究室

部室員

  • 原 聡史(研究員)
  • 寺尾 美穂(研究員)

業績

2018

Saito T, Hara S, Kato T, Tamano M, Muramatsu A, Asahara H, Takada S: A tandem repeat array in IG-DMR is essential for imprinting of paternal allele at the Dlk1-Dio3 domain during embryonic development. Human Molecular Genetics 27(18):3283-3292 (2018).
Tsuji-Hosokawa A, Kashimada K, Kato T, Ogawa Y, Nomura R, Takasawa K, Lavery R, Coschiera A, Schlessinger D, Harley VR, Takada S, Morio T: Peptidyl arginine deiminase 2 (Padi2) is expressed in Sertoli cells in a specific manner and regulated by SOX9 during testicular development. Scientific Reports 8(1):13263 (2018).
Osumi T, Tsujimoto SI, Tamura M, Uchiyama M, Nakabayashi K, Okamura K, Yoshida M, Tomizawa D, Watanabe A, Takahashi H, Hori T, Yamamoto S, Hamamoto K, Migita M, Ogata-Kawata H, Uchiyama T, Kizawa H, Ueno-Yokohata H, Shirai R, Seki M, Ohki K, Takita J, Inukai T, Ogawa S, Kitamura T, Matsumoto K, Hata K, Kiyokawa N, Goyama S, Kato M: Recurrent RARB translocations in acute promyelocytic leukemia lacking RARA translocation. Cancer Research 78(16):4452-4458 (2018).
Inui M, Mokuda S, Sato T, Tamano M, Takada S, Asahara H: Dissecting the roles of miR-140 and its host gene. Nature Cell Biology 20(5):516-518 (2018).
Hara S, Takada S: Genome editing for the reproduction and remedy of human diseases in mice. Journal of Human Genetics 63(2):107-113 (2018).
Katoh-Fukui Y, Yatsuga S, Shima H, Hattori A, Nakamura A, Okamura K, Yanagi K, Iso M, Kaname T, Matsubara Y, Fukami M: An unclassified variant of CHD7 activates a cryptic splice site in a patient with CHARGE syndrome. Human Genome Variation 5:18006 (2018).
Okuno M, Ayabe T, Yokota I, Musha I, Shiga K, Kikuchi T, Kikuchi N, Ohtake A, Nakamura A, Nakabayashi K, Okamura K, Momozawa Y, Kubo M, Suzuki J, Urakami T, Kawamura T, Amemiya S, Ogata T, Sugihara S, Fukami M: Protein-altering variants of PTPN2 in childhood-onset Type 1A diabetes. Diabetic Medicine 35(3):376-380 (2018).
Takasawa K, Igarashi M, Ono M, Takemoto A, Takada S, Yamataka A, Ogata T, Morio T, Fukami M, Kashimada K: Phenotypic variation in 46,XX disorders of sex development due to the NR5A1 p.R92W variant: A sibling case report and literature review. Sexual Development 11(5-6):284-288 (2018).
Steward O, Matsudaira Yee K, Farris S, Pirbhoy PS, Worley P, Okamura K, Okuno H, Bito H: Delayed degradation and impaired dendritic delivery of intron-lacking EGFP-Arc/Arg3.1 mRNA in EGFP-Arc transgenic mice. Frontiers in Molecular Neuroscience 10:435 (2018).

2017

Murakami M, Yoshimoto T, Nakabayashi K, Nakano Y, Fukaishi T, Tsuchiya K, Minami I, Bouchi R, Okamura K, Fujii Y, Hashimoto K, Hata KI, Kihara K, Ogawa Y: Molecular characteristics of the KCNJ5 mutated aldosterone-producing adenomas. Endocrine-related Cancer 24(10):531-541 (2017).
Kajiwara K, Tanemoto T, Wada S, Karibe J, Ihara N, Ikemoto Y, Kawasaki T, Oishi Y, Samura O, Okamura K, Takada S, Akutsu H, Sago H, Okamoto A, Umezawa A: Fetal therapy model of myelomeningocele with three-dimensional skin using amniotic fluid cell-derived induced pluripotent stem cells. Stem Cell Reports 8(6):1701-1713 (2017).
Hara S, Terao M, Takada S: A protocol for production of mutant mice using chemically synthesized crRNA/tracrRNA with Cas9 nickase and FokI-dCas9. Bio-protocol 7(11):e2340 (2017).
Kagami M, Matsubara K, Nakabayashi K, Nakamura A, Sano S, Okamura K, Hata K, Fukami M, Ogata T: Genome-wide multilocus imprinting disturbance analysis in Temple syndrome and Kagami-Ogata syndrome. Genetics in Medicine 19(4):476-482 (2017).
Kato T, Hara S, Goto Y, Ogawa Y, Okayasu H, Kubota S, Tamano M, Terao M, Takada S: Creation of mutant mice with megabase-sized deletions containing custom-designed breakpoints by means of the CRISPR/Cas9 system. Scientific Reports 7(1):59 (2017).
Saito T, Hara S, Tamano M, Asahara H, Takada S: Deletion of conserved sequences in IG-DMR at Dlk1-Gtl2 locus suggests their involvement in expression of paternally expressed genes in mice. The Journal of Reproduction and Development 63(1):101-109 (2017).
Sakaki M, Ebihara Y, Okamura K, Nakabayashi K, Igarashi A, Matsumoto K, Hata K, Kobayashi Y, Maehara K: Potential roles of DNA methylation in the initiation and establishment of replicative senescence revealed by array-based methylome and transcriptome analyses. PloS One 12(2):e0171431 (2017).
Inui M, Tamano M, Kato T, Takada S: CRISPR/Cas9-mediated simultaneous knockout of Dmrt1 and Dmrt3 does not recapitulate the 46,XY gonadal dysgenesis observed in 9p24.3 deletion patients. Biochemistry and Biophysics Reports 9:238-244 (2017).
Igarashi M, Takasawa K, Hakoda A, Kanno J, Takada S, Miyado M, Baba T, Morohashi KI, Tajima T, Hata K, Nakabayashi K, Matsubara Y, Sekido R, Ogata T, Kashimada K, Fukami M: Identical NR5A1 missense mutations in two unrelated 46,XX individuals with testicular tissues. Human Mutation 38(1):39-42 (2017).
Kato T, Takada S: In vivo and in vitro disease modeling with CRISPR/Cas9. Briefings in Functional Genomics 16(1):13-24 (2017).
Hirabayashi S, Ohki K, Nakabayashi K, Ichikawa H, Momozawa Y, Okamura K, Yaguchi A, Terada K, Saito Y, Yoshimi A, Ogata-Kawata H, Sakamoto H, Kato M, Fujimura J, Hino M, Kinoshita A, Kakuda H, Kurosawa H, Kato K, Kajiwara R, Moriwaki K, Morimoto T, Nakamura K, Noguchi Y, Osumi T, Sakashita K, Takita J, Yuza Y, Matsuda K, Yoshida T, Matsumoto K, Hata K, Kubo M, Matsubara Y, Fukushima T, Koh K, Manabe A, Ohara A, Kiyokawa N: ZNF384-related fusion genes define a subgroup of childhood B-cell precursor acute lymphoblastic leukemia with a characteristic immunotype. Haematologica 102(1):118-129 (2017).

2016

Akutsu H, Nasu M, Morinaga S, Motoyama T, Honma N, Machida M, Yamazaki-Inoue M, Okamura K, Nakabayashi K, Takada S, Nakamura N, Kanzaki S, Hata K, Umezawa A: In vivo maturation of human embryonic stem cell-derived teratoma over time. Regenerative Therapy 5:31-39 (2016).
Miyado M, Inui M, Igarashi M, Katoh-Fukui Y, Takasawa K, Hakoda A, Kanno J, Kashimada K, Miyado K, Tamano M, Ogata T, Takada S, Fukami M: The p.R92W variant of NR5A1/Nr5a1 induces testicular development of 46,XX gonads in humans, but not in mice: phenotypic comparison of human patients and mutation-induced mice. Biology of Sex Differences 7:56 (2016).
Hara S, Kato T, Goto Y, Kubota S, Tamano M, Terao M, Takada S: Microinjection-based generation of mutant mice with a double mutation and a 0.5 Mb deletion in their genome by the CRISPR/Cas9 system. The Journal of Reproduction and Development 62(5):531-536 (2016).
Morita S, Noguchi H, Horii T, Nakabayashi K, Kimura M, Okamura K, Sakai A, Nakashima H, Hata K, Nakashima K, Hatada I: Targeted DNA demethylation in vivo using dCas9-peptide repeat and scFv-TET1 catalytic domain fusions. Nature Biotechnology 34(10):1060-1065 (2016).
Shima H, Yatsuga S, Nakamura A, Sano S, Sasaki T, Katsumata N, Suzuki E, Hata K, Nakabayashi K, Momozawa Y, Kubo M, Okamura K, Kure S, Matsubara Y, Ogata T, Narumi S, Fukami M: NR0B1 frameshift mutation in a boy with idiopathic central precocious puberty. Sexual Development 10(4):205-209 (2016).
Nakamichi R, Ito Y, Inui M, Onizuka N, Kayama T, Kataoka K, Suzuki H, Mori M, Inagawa M, Ichinose S, Lotz MK, Sakai D, Masuda K, Ozaki T, Asahara H: Mohawk promotes the maintenance and regeneration of the outer annulus fibrosus of intervertebral discs. Nature Communications 7:12503 (2016).
Terao M, Tamano M, Hara S, Kato T, Kinoshita M, Takada S: Utilization of the CRISPR/Cas9 system for the efficient production of mutant mice using crRNA/tracrRNA with Cas9 nickase and FokI-dCas9. Experimental Animals 65(3):275-283 (2016).
Nakamura A, Hamaguchi E, Horikawa R, Nishimura Y, Matsubara K, Sano S, Nagasaki K, Matsubara Y, Umezawa A, Tajima T, Ogata T, Kagami M, Okamura K, Fukami M: Complex genomic rearrangement within the GNAS region associated with familial pseudohypoparathyroidism type 1b. The Journal of Clinical Endocrinology and Metabolism 101(7):2623-2627 (2016).
Fujinaga H, Fujinaga H, Watanabe N, Kato T, Tamano M, Terao M, Takada S, Ito Y, Umezawa A, Kuroda M: Cord blood-derived endothelial colony-forming cell function is disrupted in congenital diaphragmatic hernia. American Journal of Physiology. Lung Cellular and Molecular Physiology 310(11):L1143-1154 (2016).
Higasa K, Miyake N, Yoshimura J, Okamura K, Niihori T, Saitsu H, Doi K, Shimizu M, Nakabayashi K, Aoki Y, Tsurusaki Y, Morishita S, Kawaguchi T, Migita O, Nakayama K, Nakashima M, Mitsui J, Narahara M, Hayashi K, Funayama R, Yamaguchi D, Ishiura H, Ko WY, Hata K, Nagashima T, Yamada R, Matsubara Y, Umezawa A, Tsuji S, Matsumoto N, Matsuda F: Human genetic variation database, a reference database of genetic variations in the Japanese population. Journal of Human Genetics 61(6):547-553 (2016).
Okamura K, Sakaguchi H, Sakamoto-Abutani R, Nakanishi M, Nishimura K, Yamazaki-Inoue M, Ohtaka M, Periasamy VS, Alshatwi AA, Higuchi A, Hanaoka K, Nakabayashi K, Takada S, Hata K, Toyoda M, Umezawa A: Distinctive features of single nucleotide alterations in induced pluripotent stem cells with different types of DNA repair deficiency disorders. Scientific Reports 6:26342 (2016).
Hayashi K, Kawai YL, Yura K, Yoshida MA, Ogura A, Hata K, Nakabayashi K, Okamura K: Complete genome sequence of the mitochondrial DNA of the sparkling enope squid, Watasenia scintillans. Mitochondrial DNA 27(3):1842-3 (2016).
Miyamoto Y, Tamano M, Torii T, Kawahara K, Nakamura K, Tanoue A, Takada S, Yamauchi J: Data supporting the role of Fyn in initiating myelination in the peripheral nervous system. Data in Brief 7:1098-1105 (2016).

2015

Miyata T, Sonoda K, Tomikawa J, Tayama C, Okamura K, Maehara K, Kobayashi H, Wake N, Kato K, Hata K, Nakabayashi K: Genomic, epigenomic, and transcriptomic profiling towards identifying omics features and specific biomarkers that distinguish uterine leiomyosarcoma and leiomyoma at molecular levels. Sarcoma 2015:412068 (2015).
Tsumura H, Ito M, Takami M, Arai M, Li XK, Hamatani T, Igarashi A, Takada S, Miyado K, Umezawa A, Ito Y: Conditional deletion of CD98hc inhibits osteoclast development. Biochemistry and Biophysics Reports 5:203-210 (2015).
Okamura K, Kawai T, Hata K, Nakabayashi K: Lists of HumanMethylation450 BeadChip probes with nucleotide-variant information obtained from the Phase 3 data of the 1000 Genomes Project. Genomics Data 7:67-69 (2015).
Miyamoto Y, Torii T, Takada S, Ohno N, Saitoh Y, Nakamura K, Ito A, Ogata T, Terada N, Tanoue A, Yamauchi J: Involvement of the Tyro3 receptor and its intracellular partner Fyn signaling in Schwann cell myelination. Molecular Biology of the Cell 26(19):3489-3503 (2015).
Kawai T, Yamada T, Abe K, Okamura K, Kamura H, Akaishi R, Minakami H, Nakabayashi K, Hata K: Increased epigenetic alterations at the promoters of transcriptional regulators following inadequate maternal gestational weight gain. Scientific Reports 5:14224 (2015).
Yokoyama T, Miura F, Araki H, Okamura K, Ito T: Changepoint detection in base-resolution methylome data reveals a robust signature of methylated domain landscape. BMC Genomics 16:594 (2015).
Okamura K, Toyoda M, Hata K, Nakabayashi K, Umezawa A: Whole-exome sequencing of fibroblast and its iPS cell lines derived from a patient diagnosed with xeroderma pigmentosum. Genomics Data 6:4-6 (2015).
Katoh-Fukui Y, Igarashi M, Nagasaki K, Horikawa R, Nagai T, Tsuchiya T, Suzuki E, Miyado M, Hata K, Nakabayashi K, Hayashi K, Matsubara Y, Baba T, Morohashi K, Igarashi A, Ogata T, Takada S, Fukami M: Testicular dysgenesis/regression without campomelic dysplasia in patients carrying missense mutations and upstream deletion of SOX9. Molecular Genetics & Genomic Medicine 3(6):550-557 (2015).
Hara S, Tamano M, Yamashita S, Kato T, Saito T, Sakuma T, Yamamoto T, Inui M, Takada S: Generation of mutant mice via the CRISPR/Cas9 system using FokI-dCas9. Scientific Reports 5:11221 (2015).
Matsubara Y, Kato T, Kashimada K, Tanaka H, Zhi Z, Ichinose S, Mizutani S, Morio T, Chiba T, Ito Y, Saga Y, Takada S, Asahara H: TALEN-mediated gene disruption on Y chromosome reveals critical role of EIF2S3Y in mouse spermatogenesis. Stem Cells and Development 24(10):1164-1170 (2015).
Otabe K, Nakahara H, Hasegawa A, Matsukawa T, Ayabe F, Onizuka N, Inui M, Takada S, Ito Y, Sekiya I, Muneta T, Lotz M, Asahara H: Transcription factor Mohawk controls tenogenic differentiation of bone marrow mesenchymal stem cells in vitro and in vivo. Journal of Orthopaedic Research 33(1):1-8 (2015).
Miyata K, Miyata T, Nakabayashi K, Okamura K, Naito M, Kawai T, Takada S, Kato K, Miyamoto S, Hata K, Asahara H: DNA methylation analysis of human myoblasts during in vitro myogenic differentiation: de novo methylation of promoters of muscle-related genes and its involvement in transcriptional down-regulation. Human Molecular Genetics 24(2):410-423 (2015).
Kawai YL, Yura K, Shindo M, Kusakabe R, Hayashi K, Hata K, Nakabayashi K, Okamura K: Complete genome sequence of the mitochondrial DNA of the river lamprey, Lethenteron japonicum. Mitochondrial DNA 26(6):863-864 (2015).

2014

Nagata E, Kano H, Kato F, Yamaguchi R, Nakashima S, Takayama S, Kosaki R, Tonoki H, Mizuno S, Watanabe S, Yoshiura K, Kosho T, Hasegawa T, Kimizuka M, Suzuki A, Shimizu K, Ohashi H, Haga N, Numabe H, HoriiE, Nagai T, Yoshihashi H, Nishimura G, Toda T, Takada S, Yokoyama S, Asahara H, Sano S, Fukami M, Ikegawa S, Ogata T: Japanese founderduplications/triplications involving BHLHA9 are associated with split-hand/footmalformation with or without long bone deficiency and Gollop-Wolfgang complex. Orphanet Journal of Rare Diseases 9:125 (2014).
Miyata K, Yotsumoto F, Nam SO, Odawara T, Manabe S, Ishikawa T, Itamochi H, Kigawa J, Takada S, Asahara H, Kuroki M, Miyamoto S: Contribution of transcription factor, SP1, to the promotion of HB-EGF expression in defense mechanism against the treatment of irinotecan in ovarian clear cell carcinoma. Cancer Medicine 3(5):1159-1169 (2014).
Torii T, Miyamoto Y, Takada S, Tsumura H, Arai M, Nakamura K, Ohbuchi K, Yamamoto M, Tanoue A, Yamauchi J: In vivo knockdown of ErbB3 in mice inhibits Schwann cell precursor migration. Biochemical and Biophysical Research Communications 452(3):782-788 (2014).
Fukawatase Y, Toyoda M, Okamura K, Nakamura K, Nakabayashi K, Takada S, Yamazaki-Inoue M, Masuda A, Nasu M, Hata K, Hanaoka K, Higuchi A, Takubo K, Umezawa A: Ataxia telangiectasia derived iPS cells show preserved x-ray sensitivity and decreased chromosomal instability. Scientific Reports 4:5421 (2014).
Inui M, Miyado M, Igarashi M, Tamano M, Kubo A, Yamashita S, Asahara H, Fukami M, Takada S: Rapid generation of mouse models with defined point mutations by the CRISPR/Cas9 system. Scientific Reports 4:5396 (2014).
Migita O, Maehara K, Kamura H, Miyakoshi K, Tanaka M, Morokuma S, Fukushima K, Shimamoto T, Saito S, Sago H, Nishihama K, Abe K, Nakabayashi K, Umezawa A, Okamura K, Hata K: Compilation of copy number variants identified in phenotypically normal and parous Japanese women. Journal of Human Genetics 59(6):326-331 (2014).
Matsubara Y, Chiba T, Kashimada K, Morio T, Takada S, Mizutani S, Asahara H: Transcription activator-like effector nuclease-mediated transduction of exogenous gene into IL2RG locus. Scientific Reports 4:5043 (2014).
Court F, Tayama C, Romanelli V, Martin-Trujillo A, Iglesias-Platas I, Okamura K, Sugahara N, Simón C, Moore H, Harness JV, Keirstead H, Sanchez-Mut JV, Kaneki E, Lapunzina P, Soejima H, Wake N, Esteller M, Ogata T, Hata K, Nakabayashi K, Monk D: Genome-wide parent-of-origin DNA methylation analysis reveals the intricacies of human imprinting and suggests a germline methylation-independent mechanism of establishment. Genome Research 24(4):554-569 (2014).
Onizuka N, Ito Y, Inagawa M, Nakahara H, Takada S, Lotz M, Toyama Y, Asahara H: The Mohawk homeobox transcription factor regulates the differentiation of tendons and volar plates. Journal of Orthopaedic Science 19(1):172-180 (2014).

2013

Kato T, Miyata K, Sonobe M, Yamashita S, Tamano M, Miura K, Kanai Y, Miyamoto S, Sakuma T, Yamamoto T, Inui M, Kikusui T, Asahara H, Takada S: Production of Sry knockout mouse using TALEN via oocyte injection. Scientific Reports 3:3136 (2013).
Takada S, Sato T, Ito Y, Yamashita S, Kato T, Kawasumi M, Kanai-Azuma M, Igarashi A, Kato T, Tamano M, Asahara H: Targeted gene deletion of miRNAs in mice by TALEN system. PloS One 8(10):e76004 (2013).
Shimizu H, Kubo A, Uchibe K, Hashimoto M, Yokoyama S, Takada S, Mitsuoka K, Asahara H: The AERO system: a 3D-like approach for recording gene expression patterns in the whole mouse embryo. PloS One 8(10):e75754 (2013).
Rakoczy J, Fernandez-Valverde SL, Glazov EA, Wainwright EN, Sato T, Takada S, Combes AN, Korbie DJ, Miller D, Grimmond SM, Little MH, Asahara H, Mattick JS, Taft RJ, Wilhelm D: MicroRNAs-140-5p/140-3p modulate Leydig cell numbers in the developing mouse testis. Biology of Reproduction 88(6):143 (2013).

2012

Takada S, Asahara H: Current strategies for microRNA research. Modern Rheumatology 22(5):645-653 (2012).
Fukami M#, Tsuchiya T#, Takada S#, Kanbara A, Asahara H, Igarashi A, Kamiyama Y, Nishimura G, Ogata T: Complex genomic rearrangement in the SOX9 5' region in a patient with Pierre Robin sequence and hypoplastic left scapula. American Journal of Medical Genetics. Part A 158A(7):1529-1534 (2012). (#equal first authors)
Yamashita S, Miyaki S, Kato Y, Yokoyama S, Sato T, Barrionuevo F, Akiyama H, Scherer G, Takada S, Asahara H: L-Sox5 and Sox6 proteins enhance chondrogenic miR-140 microRNA expression by strengthening dimeric Sox9 activity. The Journal of Biological Chemistry 287(26):22206-22215 (2012).