機能ゲノム医学研究室(石田研究室）
Functional Genomics and Medicine
研究内容 Research
分泌型HtrAファミリーの機能解明 〜遺伝子から病態解明へ〜(岡助教）
私達は、マウスやヒトが持つHtrA1（High temperature requirement A 1）という遺伝子を解析しています。HtrA1は細胞外に分泌されて働くセリンプロテアーゼです。HtrA1の名前はバクテリアの相同遺伝子が持つ機能に由来しています。バクテリアのHtrAはバクテリアが高温化で生存するために必須の遺伝子で、高温によって異常になった蛋白質の構造を修正（Refolding）したり分解する機能を持つHeat shock proteinをコードしています。
ヒトのHtrA1は様々な疾患と関連していることが示されています。変形性関節炎やリウマチ性関節炎の患者さんの関節軟骨や関節液の中では関節炎に伴ってHtrA1の発現が増加します。HtrA1は関節軟骨の構成成分であるプロテオグリカン等を分解する活性を持つことから関節炎の悪化因子ではないかと考えられています。また、加齢黄斑変性は加齢に伴って起こるヒトの網膜の変性疾患で先進国では高齢者の失明原因として重要ですが、発症にはHtrA1遺伝子の一塩基多型（SNP）が強くリンクしていることがわかっています。加齢黄斑変性に関連するHtrA1遺伝子のSNPはプロモーター領域にあり、HtrA1の発現を上昇させると考えられています。さらに、HtrA1遺伝子の変異によりCARASILと呼ばれる遺伝性の脳梗塞になることがわかってきました。その他、妊娠性高血圧症やがんに関わることも示めされています。
以上のようにHtrA1の発現の異常は様々な病気に関わりますが、そのメカニズムに関してはほとんどわかっていません。私たちはHtrA1ノックアウトマウスをツールとして用いながら、HtrA1遺伝子が関連する病気の病態を分子レベルで説明することを目指して研究を行っています。
論文リスト
Cardiac fibroblasts regulate the development of heart failure via
Htra3-TGF-β-IGFBP7 axis. [https://pubmed.ncbi.nlm.nih.go
Ko T, Nomura S, Yamada S, Fujita K, Fujita T, Satoh M, Oka C, Katoh M,
Ito M, Katagiri M, Sassa T, Zhang B, Hatsuse S, Yamada T, Harada M, Toko
H, Amiya E, Hatano M, Kinoshita O, Nawata K, Abe H, Ushiku T, Ono M,
Ikeuchi M, Morita H, Aburatani H, Komuro I.
Nat Commun. 2022 Jun 7;13(1):3275. doi: 10.1038/s41467-022-30630-y.
PMID: 35672400 Free PMC article.
Interplay between HTRA1 and classical signalling pathways in
organogenesis and diseases. [https://pubmed.ncbi.nlm.nih.go
Oka C, Saleh R, Bessho Y, Reza HM.
Saudi J Biol Sci. 2022 Apr;29(4):1919-1927. doi:
10.1016/j.sjbs.2021.11.056. Epub 2021 Dec 1. PMID: 35531175 Free PMC
article. Review.
Association of the HtrA1 rs11200638 Polymorphism with Neovascular
Age-Related Macular Degeneration in Indonesia. [https://pubmed.ncbi.nlm.nih.go
Supanji S, Perdamaian ABI, Romdhoniyyah DF, Sasongko MB, Agni AN,
Wardhana FS, Widayanti TW, Prayogo ME, Oka C, Kawaichi M.
Ophthalmol Ther. 2022 Feb;11(1):125-133. doi:
10.1007/s40123-021-00402-w. Epub 2021 Nov 2. PMID: 34727349 Free PMC
article.
HtrA1 meets NETs: does it open a new field? [https://pubmed.ncbi.nlm.nih.go
Oka C, Kawaichi M.
Blood. 2021 Sep 16;138(11):920-921. doi: 10.1182/blood.2021013025. PMID:
34529018 No abstract available.
Associations of _ARMS2_ and _CFH_ Gene Polymorphisms with Neovascular
Age-Related Macular Degeneration. [https://pubmed.ncbi.nlm.nih.go
Supanji S, Romdhoniyyah DF, Sasongko MB, Agni AN, Wardhana FS, Widayanti
TW, Prayogo ME, Perdamaian ABI, Dianratri A, Kawaichi M, Oka C.
Clin Ophthalmol. 2021 Mar 11;15:1101-1108. doi: 10.2147/OPTH.S298310.
eCollection 2021. PMID: 33737801 Free PMC article.
Loss of the serine protease HTRA1 impairs smooth muscle cells
maturation. [ https://pubmed.ncbi.nlm.nih.go
Klose R, Prinz A, Tetzlaff F, Weis EM, Moll I, Rodriguez-Vita J, Oka C,
Korff T, Fischer A.
Sci Rep. 2019 Dec 3;9(1):18224. doi: 10.1038/s41598-019-54807-6. PMID:
31796853 Free PMC article.
High-Temperature Requirement A1 Protease as a Rate-Limiting Factor in
the Development of Osteoarthritis. [ https://pubmed.ncbi.nlm.nih.go
Chen PH, Tang T, Liu C, Wang B, Mian M, Oka C, Baquerizo M, Li Y, Xu L.
Am J Pathol. 2019 Jul;189(7):1423-1434. doi:
10.1016/j.ajpath.2019.03.013. Epub 2019 Apr 30. PMID: 31051168
Loss of HtrA1 serine protease induces synthetic modulation of aortic
vascular smooth muscle cells. [https://pubmed.ncbi.nlm.nih.go
Ikawati M, Kawaichi M, Oka C.
PLoS One. 2018 May 16;13(5):e0196628. doi: 10.1371/journal.pone.0196628.
eCollection 2018. PMID: 29768431 Free PMC article.
CADASIL brain vessels show a HTRA1 loss-of-function profile. [ https://pubmed.ncbi.nlm.nih.go
Zellner A, Scharrer E, Arzberger T, Oka C, Domenga-Denier V, Joutel A,
Lichtenthaler SF, Müller SA, Dichgans M, Haffner C.
Acta Neuropathol. 2018 Jul;136(1):111-125. doi:
10.1007/s00401-018-1853-8. Epub 2018 May 3. PMID: 29725820
Inactivation of the serine protease HTRA1 inhibits tumor growth by
deregulating angiogenesis. [ https://pubmed.ncbi.nlm.nih.go
Klose R, Adam MG, Weis EM, Moll I, Wüstehube-Lausch J, Tetzlaff F, Oka
C, Ehrmann M, Fischer A.
Oncogene. 2018 Aug;37(31):4260-4272. doi: 10.1038/s41388-018-0258-4.
Epub 2018 May 1. PMID: 29713059
BMP-Responsive Protease HtrA1 Is Differentially Expressed in Astrocytes
and Regulates Astrocytic Development and Injury Response. [https://pubmed.ncbi.nlm.nih.go
Chen J, Van Gulden S, McGuire TL, Fleming AC, Oka C, Kessler JA, Peng
CY.
J Neurosci. 2018 Apr 11;38(15):3840-3857. doi:
10.1523/JNEUROSCI.2031-17.2018
PMC article.
Role of HTRA1 in bone formation and regeneration: In vitro and in vivo
evaluation. [https://pubmed.ncbi.nlm.nih.go
Filliat G, Mirsaidi A, Tiaden AN, Kuhn GA, Weber FE, Oka C, Richards PJ.
PLoS One. 2017 Jul 21;12(7):e0181600. doi: 10.1371/journal.pone.0181600.
eCollection 2017. PMID: 28732055 Free PMC article.
Epigenetic silencing of serine protease HTRA1 drives polyploidy. [ https://pubmed.ncbi.nlm.nih.go
Schmidt N, Irle I, Ripkens K, Lux V, Nelles J, Johannes C, Parry L,
Greenow K, Amir S, Campioni M, Baldi A, Oka C, Kawaichi M, Clarke AR,
Ehrmann M.
BMC Cancer. 2016 Jul 7;16:399. doi: 10.1186/s12885-016-2425-8. PMID:
27388476 Free PMC article.
HTRA1 (high temperature requirement A serine peptidase 1) gene is
transcriptionally regulated by insertion/deletion nucleotides located at
the 3' end of the ARMS2 (age-related maculopathy susceptibility 2) gene
in patients with age-related macular degeneration. [https://pubmed.ncbi.nlm.nih.go
Iejima D, Itabashi T, Kawamura Y, Noda T, Yuasa S, Fukuda K, Oka C,
Iwata T.
J Biol Chem. 2015 Jan 30;290(5):2784-97. doi: 10.1074/jbc.M114.593384.
Epub 2014 Dec 17. PMID: 25519903 Free PMC article.
Abnormal development of placenta in HtrA1-deficient mice. [ https://pubmed.ncbi.nlm.nih.go
Hasan MZ, Ikawati M, Tocharus J, Kawaichi M, Oka C.
Dev Biol. 2015 Jan 1;397(1):89-102. doi: 10.1016/j.ydbio.2014.10.015.
Epub 2014 Oct 27. PMID: 25446274
HtrA1 is induced by oxidative stress and enhances cell senescence
through p38 MAPK pathway. [https://pubmed.ncbi.nlm.nih.go
Supanji, Shimomachi M, Hasan MZ, Kawaichi M, Oka C.
Exp Eye Res. 2013 Jul;112:79-92. doi: 10.1016/j.exer.2013.04.013. Epub
2013 Apr 24. PMID: 23623979
High temperature requirement factor A1 (HTRA1) gene regulates
angiogenesis through transforming growth factor-β family member growth
differentiation factor 6. [ https://pubmed.ncbi.nlm.nih.go
Zhang L, Lim SL, Du H, Zhang M, Kozak I, Hannum G, Wang X, Ouyang H,
Hughes G, Zhao L, Zhu X, Lee C, Su Z, Zhou X, Shaw R, Geum D, Wei X, Zhu
J, Ideker T, Oka C, Wang N, Yang Z, Shaw PX, Zhang K.
J Biol Chem. 2012 Jan 6;287(2):1520-6. doi: 10.1074/jbc.M111.275990.
Epub 2011 Nov 2. PMID: 22049084 Free PMC article. Clinical Trial.
Increased expression of multifunctional serine protease, HTRA1, in
retinal pigment epithelium induces polypoidal choroidal vasculopathy in
mice. [https://pubmed.ncbi.nlm.nih.go
Jones A, Kumar S, Zhang N, Tong Z, Yang JH, Watt C, Anderson J, Amrita,
Fillerup H, McCloskey M, Luo L, Yang Z, Ambati B, Marc R, Oka C, Zhang
K, Fu Y.
Proc Natl Acad Sci U S A. 2011 Aug 30;108(35):14578-83. doi:
10.1073/pnas.1102853108. Epub 2011 Aug 15. PMID: 21844367 Free PMC
article.
Expression of mouse HtrA1 serine protease in normal bone and cartilage
and its upregulation in joint cartilage damaged by experimental
arthritis. [ https://pubmed.ncbi.nlm.nih.go
Tsuchiya A, Yano M, Tocharus J, Kojima H, Fukumoto M, Kawaichi M, Oka C.
Bone. 2005 Sep;37(3):323-36. doi: 10.1016/j.bone.2005.03.015. PMID:
15993670
Developmentally regulated expression of mouse HtrA3 and its role as an
inhibitor of TGF-beta signaling. [ https://pubmed.ncbi.nlm.nih.go
Tocharus J, Tsuchiya A, Kajikawa M, Ueta Y, Oka C, Kawaichi M.
Dev Growth Differ. 2004 Jun;46(3):257-74. doi:
10.1111/j.1440-169X.2004.00743
Binding of proteins to the PDZ domain regulates proteolytic activity of
HtrA1 serine protease. [https://pubmed.ncbi.nlm.nih.go
Murwantoko, Yano M, Ueta Y, Murasaki A, Kanda H, Oka C, Kawaichi M.
Biochem J. 2004 Aug 1;381(Pt 3):895-904. doi: 10.1042/BJ20040435. PMID:
15101818 Free PMC article.
HtrA1 serine protease inhibits signaling mediated by Tgfbeta family
proteins. [ https://pubmed.ncbi.nlm.nih.go
Oka C, Tsujimoto R, Kajikawa M, Koshiba-Takeuchi K, Ina J, Yano M,
Tsuchiya A, Ueta Y, Soma A, Kanda H, Matsumoto M, Kawaichi M.
Development. 2004 Mar;131(5):1041-53. doi: 10.1242/dev.00999. PMID:
14973287
Disruption of the mouse RBP-J kappa gene results in early embryonic
death. [ https://pubmed.ncbi.nlm.nih.go
Oka C, Nakano T, Wakeham A, de la Pompa JL, Mori C, Sakai T, Okazaki S,
Kawaichi M, Shiota K, Mak TW, Honjo T.
Development. 1995 Oct;121(10):3291-301. doi: 10.1242/dev.121.10.3291.
PMID: 7588063
V(D)J recombination of immunoglobulin genes. [ https://pubmed.ncbi.nlm.nih.go
Oka C, Kawaichi M.
Adv Biophys. 1995;31:163-80. doi: 10.1016/0065-227x(95)99390-b. PMID:
7625272 Review.
