2003 Fiscal Year Annual Research Report

疾患モデル動物の体系的遺伝子発現解析による創薬標的分子の同定

Research Project

Project/Area Number	14370039
Research Institution	KYOTO UNIVERSITY
Principal Investigator	辻本豪三京都大学, 薬学研究科, 教授 (80172013)
Co-Investigator(Kenkyū-buntansha)	三輪嘉尚京都大学, 薬学研究科, 講師 (20093320) 松本治京都大学, 薬学研究科, 助教授 (10231599)
Keywords	cDNAチップ / 疾患動物モデル / 標準化cDNAライブラリー / ラット腎臓
Research Abstract	本研究ではその遺伝子情報が未だ充実していない動物モデル(ラット、モルモット)の各臓器別標準化cDNAライブラリーを作成し、このライブラリーを高密度に配置した臓器別標準cDNAライブラリーDNAチップを作成し、モデル疾患における病態遺伝子発現の解析と既存の薬物治療により変動する発現遺伝子群を絞り込むことを目的とした。具体的計画には、初年度マイクロアレイによる標準化cDNAチップの作成方法の確立を、2年度を用いて病態動物モデルを解析する。初年度、ラット、マウスの各臓器より標準化cDNAライブラリーを作製した。作成された各臓器の標準化ライブラリーの内約数万クローンをチップ化する事により、各臓器において発現する全遺伝子群をカタログ化したチップを作成した。このチップを用いて疾患動物モデルで遺伝子発現の変動をモニター解析し、病態関連遺伝子群、治療関連遺伝子群を絞り上げを実施し病態生理上の意義を検討した。具体的にはラット糸球体基底膜を抗原とするウサギ抗血清をラットに投与することにより,ラット糸球体腎炎モデルを作製した。糸球体腎炎の誘発は,ラットに上記の腎炎誘発用の抗血清投与液を静脈内投与することにより行い、同時に糸球体腎炎マーカーとしては,尿蛋白および血中クレアチニン濃度、並びに病理組織を測定し、モデル作製の成否について確認した。このモデルでラット腎臓標準化cDNAマイクロアレイチップを用いて,ラット糸球体腎炎モデルの腎臓組織において発現量が変動する遺伝子、腎臓組織における発現変動遺伝子を解析した。その結果、腎疾患の病態形成,病状の悪化や治療のターゲットに関連する可能性の極めて高い遺伝子群を見出すことができた。以上のことから、この方法論は病態解析、創薬ターゲットの絞り込みに有効な方法論であことが明かとなった。

Research Products

(22 results)

All Other

All Publications (22 results)

[Publications] Shibata K: "Alphal-Adrenergic receptor subtypes differentially control cell cycle of transfected CHO cells through a cAMP-dependent mechanism involving p27Kipl"J.Biol.Chem.. 278. 672-678 (2003)
[Publications] Katsuma S: "Transcriptional profiling of gene expression patterns during sphingosine 1-phosphate-induced mesangial cell proliferation"Biochem.Biophys.Res.Commun.. 300. 577-584 (2003)
[Publications] Ishiwata H: "Characterization of Gene Expression Profiles in Early Bovine Pregnancy Using a Custom cDNA Microarray"Mol.Reprod.Dev.. 65. 9-18 (2003)
[Publications] Yoshida N: "Determination of a novel haplotype of β2-adrenergic receptor in the Japanese population by the combination of the electronic microchip assay using the NanoChip system with allele-specific PCR"Drug Metabolism and Pharmacokinetics. 17. 532-539 (2003)
[Publications] Koshimizu TA: "Recent advances in alphal-adrenoceptor pharmacology"Pharmacol.Ther.. 98. 235-244 (2003)
[Publications] Nakamura T: "Temporal gene expression changes of adipogenesis in human mesenchymal stem cells"Biochem.Biophys.Res.Commun.. 303. 306-312 (2003)
[Publications] Tanoue A: "Insights into alphal-adrenoceptor function in health and disease from transgenic animal studies"Trends in Endocrinology and Metabolism. 14. 107-113 (2003)
[Publications] Chalothorn D: "Differential cardiovascular regulatory activities of the alpha1B- and alpha1D-adrenoceptor subtypes"J.Pharmacol.Exp.Ther.. 305. 1045-1053 (2003)
[Publications] Richardson J: "Agonist-specific coupling of a cloned human alpha(1A)-adrenoceptor to different second messenger pathways"Naunyn-Schmiedeberg's Arch.. 367. 333-341 (2003)
[Publications] Ogawa K: "Analysis of gene expression in peripheral blood eosinophils from patients with atopic dermatitis and in vitro cytokine-stimulated blood eosinophils"Clin.Exp.Immunol.. 131. 436-445 (2003)
[Publications] Fukuhara Y: "Gene expression profiles in the regenerating rata liver after partial hepatectomy"J.Hepatology.. 38. 784-792 (2003)
[Publications] Yamada M: "Granzyme A mediates glucocorticoid-induced apoptosis in leukemia cells"FASEB.Journal. 17. 1712-1714 (2003)
[Publications] Hasida R: "Analysis of Gene Expression in Peripheral Blood Eosinophils from Patients with Atopic Dermatitis by Differential Display"Int.Arch.Allergy.Immunol. 131. 26-33 (2003)
[Publications] Endo F: "animal models reveal pathophysiologies of tyrosinemias"J.Nutr.. 133. 2063-2067 (2003)
[Publications] Harasawa I: "Responses To Noxious Stimuli in Mice Lacking α4d-Adrenergic Receptors"Neuro Report. 14. 1857-1860 (2003)
[Publications] Nagata N: "Analysis of highly expressed genes in monocytes from atopic dermatitis patients"Int.Arch.Allergy.Immunol.. 132. 156-167 (2003)
[Publications] Oshikawa S: "Vasopressin stimulates insulin release from islet cells through V4b receptors : A combined pharmacological/knockout approach"Mol.Pharmacol.. 65. 623-629 (2004)
[Publications] Tanoue A: "The vasopressin V1b receptor critically regulates hypothalamic-pituitary-adrenal axis activity under both stress and resting conditions"J.Clin.Invest.. 113. 302-309 (2004)
[Publications] Herath CB: "Pregnancy-associated changes in genome-wide gene expression profiles in the liver of cow throughout pregnancy"Biochem.Biophys.Res.Commun.. 313. 666-680 (2004)
[Publications] Yaguma K: "Crystallization and preliminary X-ray diffraction studies of DNA decamer d (CCAGGCCTGG) complexed with cobalt (III)-pepleomycin"Acta Crystallogr.D.Biol.Crystallogr.. 60. 144-145 (2004)
[Publications] 辻本豪三: "薬物動態研究ガイド-創薬から臨床へ-"エル・アイ・シー. 11 (2003)
[Publications] 辻本豪三: "薬物療法学"南江堂. 3 (2003)

2003 Fiscal Year Annual Research Report

疾患モデル動物の体系的遺伝子発現解析による創薬標的分子の同定

Principal Investigator

辻本 豪三 京都大学, 薬学研究科, 教授 (80172013)

Research Products

[Publications] Shibata K: "Alphal-Adrenergic receptor subtypes differentially control cell cycle of transfected CHO cells through a cAMP-dependent mechanism involving p27Kipl"J.Biol.Chem.. 278. 672-678 (2003)

[Publications] Katsuma S: "Transcriptional profiling of gene expression patterns during sphingosine 1-phosphate-induced mesangial cell proliferation"Biochem.Biophys.Res.Commun.. 300. 577-584 (2003)

[Publications] Ishiwata H: "Characterization of Gene Expression Profiles in Early Bovine Pregnancy Using a Custom cDNA Microarray"Mol.Reprod.Dev.. 65. 9-18 (2003)

[Publications] Yoshida N: "Determination of a novel haplotype of β2-adrenergic receptor in the Japanese population by the combination of the electronic microchip assay using the NanoChip system with allele-specific PCR"Drug Metabolism and Pharmacokinetics. 17. 532-539 (2003)

[Publications] Koshimizu TA: "Recent advances in alphal-adrenoceptor pharmacology"Pharmacol.Ther.. 98. 235-244 (2003)

[Publications] Nakamura T: "Temporal gene expression changes of adipogenesis in human mesenchymal stem cells"Biochem.Biophys.Res.Commun.. 303. 306-312 (2003)

[Publications] Tanoue A: "Insights into alphal-adrenoceptor function in health and disease from transgenic animal studies"Trends in Endocrinology and Metabolism. 14. 107-113 (2003)

[Publications] Chalothorn D: "Differential cardiovascular regulatory activities of the alpha1B- and alpha1D-adrenoceptor subtypes"J.Pharmacol.Exp.Ther.. 305. 1045-1053 (2003)

[Publications] Richardson J: "Agonist-specific coupling of a cloned human alpha(1A)-adrenoceptor to different second messenger pathways"Naunyn-Schmiedeberg's Arch.. 367. 333-341 (2003)

[Publications] Ogawa K: "Analysis of gene expression in peripheral blood eosinophils from patients with atopic dermatitis and in vitro cytokine-stimulated blood eosinophils"Clin.Exp.Immunol.. 131. 436-445 (2003)

[Publications] Fukuhara Y: "Gene expression profiles in the regenerating rata liver after partial hepatectomy"J.Hepatology.. 38. 784-792 (2003)

[Publications] Yamada M: "Granzyme A mediates glucocorticoid-induced apoptosis in leukemia cells"FASEB.Journal. 17. 1712-1714 (2003)

[Publications] Hasida R: "Analysis of Gene Expression in Peripheral Blood Eosinophils from Patients with Atopic Dermatitis by Differential Display"Int.Arch.Allergy.Immunol. 131. 26-33 (2003)

[Publications] Endo F: "animal models reveal pathophysiologies of tyrosinemias"J.Nutr.. 133. 2063-2067 (2003)

[Publications] Harasawa I: "Responses To Noxious Stimuli in Mice Lacking α4d-Adrenergic Receptors"Neuro Report. 14. 1857-1860 (2003)

[Publications] Nagata N: "Analysis of highly expressed genes in monocytes from atopic dermatitis patients"Int.Arch.Allergy.Immunol.. 132. 156-167 (2003)

[Publications] Oshikawa S: "Vasopressin stimulates insulin release from islet cells through V4b receptors : A combined pharmacological/knockout approach"Mol.Pharmacol.. 65. 623-629 (2004)

[Publications] Tanoue A: "The vasopressin V1b receptor critically regulates hypothalamic-pituitary-adrenal axis activity under both stress and resting conditions"J.Clin.Invest.. 113. 302-309 (2004)

[Publications] Herath CB: "Pregnancy-associated changes in genome-wide gene expression profiles in the liver of cow throughout pregnancy"Biochem.Biophys.Res.Commun.. 313. 666-680 (2004)

[Publications] Yaguma K: "Crystallization and preliminary X-ray diffraction studies of DNA decamer d (CCAGGCCTGG) complexed with cobalt (III)-pepleomycin"Acta Crystallogr.D.Biol.Crystallogr.. 60. 144-145 (2004)

[Publications] 辻本豪三: "薬物動態研究ガイド-創薬から臨床へ-"エル・アイ・シー. 11 (2003)

[Publications] 辻本豪三: "薬物療法学"南江堂. 3 (2003)

辻本豪三京都大学, 薬学研究科, 教授 (80172013)