2001 年度実績報告書

メサンギウム細胞特異的機能遺伝子群のポストゲノム研究とそれに基づくゲノム創薬

研究課題

研究課題/領域番号	13307032
研究機関	東海大学
研究代表者	黒川清東海大学, 医学部, 教授 (30167390)
研究分担者	稲城玲子東海大学, 総合医学研究所, 講師 (50232509) 宮田敏男東海大学, 医学部, 助教授 (10222332)
キーワード	メサンギウム細胞 / メグシン / セルピン / メサンギウム基質 / トランスジェニックマウス / 転写因子
研究概要	メサンギウム細胞特異的高発現遺伝子、メグシンはセルピン(serine protease inhibitor)に属し、セリンプロテアーゼ活性阻害能を有することが示唆されている。そこでメグシンの生理活性を解明する目的で、メグシンリガンド(メグシンの標的セリンプロテアーゼ)の検索を行った。結果、メグシンは弱いながらいくつかの既知のセリンプロテアーゼの酵素活性を特異的に抑制することが明らかとなり、メグシンの機能の一端が明らかにされた。またメグシンの糸球体における機能を分子レベルで解明するために、メグシンTgと同腹野生型マウスからメサンギウム細胞を単離培養し、DNA chipによる発現遺伝子プロファイルを作製、両群において発現変動がみられる遺伝子群の検索を行った。予備的な解析結果から、いくつかの遺伝子、特にメサンギウム基質のリモデリングに関与するプロテアーゼや細胞増殖に関与する転写因子などの発現変動が確認でき、メグシンTgにおける腎炎自然発症(メサンギウム細胞増殖、メサンギウム基質増生、免疫複合体沈着)の分子機序解明の手がかりが得られた。さらにメグシンのメサンギウム細胞特異的転写機構の解明を目指して、転写開始点上流域約6キロの転写活性を解析したところ、この領域だけでは細胞特性を決定することができないものの、いくつかの既知の転写因子結合モチーフがメグシン転写レベルを制御していることが明らかとなった。このことから糸球体障害時のメグシン発現亢進機序解明の手がかりが得られた。

研究成果
(23件)

すべてその他

すべて文献書誌 (23件)

[文献書誌] Miyata T, et al.: "Reactive carbonyl compound-related uremic toxicity(carbonyl stress)"Kidney Int. 59[Suppl 78]. 25-31 (2001)
[文献書誌] Miyata T, et al.: "Advanced glycation and lipoxidation end products:reactive carbonyl compounds-related uraemic toxicity"Nephrol Dial Transplant. 16[Suppl 4]. 8-11 (2001)
[文献書誌] Miyata T, et al.: "Reactive carbonyl compounds as uremic toxins"Contrib Nephrol. 133. 71-80 (2001)
[文献書誌] Ueda Y, et al.: "Does removal of glucose lower the carbonyl stress of glucose containing peritoneal dialysis?:effect of dwell time on icodextrin and amino acid PD fluids"Kidney Int. 58. 2518-2524 (2001)
[文献書誌] Yamada K, et al.: "Clusterin is up-regulated in glomerular mesangial cells in complement-mediated injury"Kidney Int. 59. 137-146 (2001)
[文献書誌] Nangaku M, et al.: "Cloning of rodent megsin revealed its up-regulation on mesangioproliferative nephritis"Kidney Int. 60. 641-652 (2001)
[文献書誌] Suzuki D, et al.: "Carbonyl Stress,Type-2 diabetic nephropathy in Japan from bench to bedside"Contributions to Nephrology. 13. 36-45 (2001)
[文献書誌] Inagi R, et al.: "Specific tissue distribution of megsin,a novel serpin,in the glomerulus and its up-regulation in IgA nephropathy"Biochem Biophys Res Commun. 286. 1098-1106 (2001)
[文献書誌] Shao J, et al.: "Protective role of nitric oxide in a model of thrombotic microangiopathy in rats"J Am Soc Nephrol. 12. 2088-2097 (2001)
[文献書誌] Miyata T, et al.: "Glyoxalase I deficiency is associated with an unusual level of advanced glycation end products in a hemodialysis patient"Kidney Int. 60. 2351-2359 (2001)
[文献書誌] Wada T, et al.: "Cloning and characterization of a novel subunit of protein serine/threonine phosphatase 4 from mesangial cells"J Am Soc Nephrol. 12. 2601-2608 (2001)
[文献書誌] Akhand AA, et al.: "Glyoxal and methylglyoxal induce aggergation and inactivation of ERK in human endothelial cells"Free Radic Biol Med. 15. 1228-1235 (2001)
[文献書誌] Miyata T, et al.: "Advances in the biochemistry and pathophysiology of the peritoneal membrane:New therapeutic insights into more biocompatible peritoneal dialysis"Kidney Int. 61. 375-386 (2001)
[文献書誌] Miyata T, et al.: ""Carbonyl Stress"and long-term uremic complications"Advanced in Nephrology. (in press).
[文献書誌] Kurokawa K, et al.: "Future perspectives of chronic renal failure"Am J Kidney Dis. (in press).
[文献書誌] Ishibashi Y, et al.: "Glucose dialysate induces mitochondrial DNA damage in peritoneal mesothelial cells"Prit Dial Int. (in press).
[文献書誌] Kurokawa K, et al.: "Current issues and future perspectives of chronic renal failure"J Am Soc Nephrol. (in press).
[文献書誌] Miyata T, et al.: "Progressive mesangial expansion and hypercellularity in transgenic mice of mesangial cell-predominant serpin,megsin"J Clin Invest. (in press).
[文献書誌] Inagi R, et al.: "Efficient detoxification of carbonyl stress by the gloxalase system in peritoneal dialysis"Kidney Int. (in press).
[文献書誌] Miyata T, et al.: "Angiotensine II receptor antagonist and angiotensine converting enzyme(ACE)inhibitor scavenge oxidative radicals and lower the formation of advanced glycation end products"J Am Soc Nephrol. (in press).
[文献書誌] Miyata T, et al.: "Massry and Glassock's Text Book of Nephrology"Alterations in nonenzymatic biochemistry of carbohydrates and lipids in uremia. 1275-1278 (2001)
[文献書誌] Nangaku M, et al.: "Forum Issue of ARS"Relevance of oxidative and carbonyl stress in uremia(in press).
[文献書誌] Miyata T, et al.: "Nutritional Management of Renal Disease"Carbonyl stress in uremia(in press).

2001 年度 実績報告書

メサンギウム細胞特異的機能遺伝子群のポストゲノム研究とそれに基づくゲノム創薬

研究代表者

黒川 清 東海大学, 医学部, 教授 (30167390)

研究成果

[文献書誌] Miyata T, et al.: "Reactive carbonyl compound-related uremic toxicity(carbonyl stress)"Kidney Int. 59[Suppl 78]. 25-31 (2001)

[文献書誌] Miyata T, et al.: "Advanced glycation and lipoxidation end products:reactive carbonyl compounds-related uraemic toxicity"Nephrol Dial Transplant. 16[Suppl 4]. 8-11 (2001)

[文献書誌] Miyata T, et al.: "Reactive carbonyl compounds as uremic toxins"Contrib Nephrol. 133. 71-80 (2001)

[文献書誌] Ueda Y, et al.: "Does removal of glucose lower the carbonyl stress of glucose containing peritoneal dialysis?:effect of dwell time on icodextrin and amino acid PD fluids"Kidney Int. 58. 2518-2524 (2001)

[文献書誌] Yamada K, et al.: "Clusterin is up-regulated in glomerular mesangial cells in complement-mediated injury"Kidney Int. 59. 137-146 (2001)

[文献書誌] Nangaku M, et al.: "Cloning of rodent megsin revealed its up-regulation on mesangioproliferative nephritis"Kidney Int. 60. 641-652 (2001)

[文献書誌] Suzuki D, et al.: "Carbonyl Stress,Type-2 diabetic nephropathy in Japan from bench to bedside"Contributions to Nephrology. 13. 36-45 (2001)

[文献書誌] Inagi R, et al.: "Specific tissue distribution of megsin,a novel serpin,in the glomerulus and its up-regulation in IgA nephropathy"Biochem Biophys Res Commun. 286. 1098-1106 (2001)

[文献書誌] Shao J, et al.: "Protective role of nitric oxide in a model of thrombotic microangiopathy in rats"J Am Soc Nephrol. 12. 2088-2097 (2001)

[文献書誌] Miyata T, et al.: "Glyoxalase I deficiency is associated with an unusual level of advanced glycation end products in a hemodialysis patient"Kidney Int. 60. 2351-2359 (2001)

[文献書誌] Wada T, et al.: "Cloning and characterization of a novel subunit of protein serine/threonine phosphatase 4 from mesangial cells"J Am Soc Nephrol. 12. 2601-2608 (2001)

[文献書誌] Akhand AA, et al.: "Glyoxal and methylglyoxal induce aggergation and inactivation of ERK in human endothelial cells"Free Radic Biol Med. 15. 1228-1235 (2001)

[文献書誌] Miyata T, et al.: "Advances in the biochemistry and pathophysiology of the peritoneal membrane:New therapeutic insights into more biocompatible peritoneal dialysis"Kidney Int. 61. 375-386 (2001)

[文献書誌] Miyata T, et al.: ""Carbonyl Stress"and long-term uremic complications"Advanced in Nephrology. (in press).

[文献書誌] Kurokawa K, et al.: "Future perspectives of chronic renal failure"Am J Kidney Dis. (in press).

[文献書誌] Ishibashi Y, et al.: "Glucose dialysate induces mitochondrial DNA damage in peritoneal mesothelial cells"Prit Dial Int. (in press).

[文献書誌] Kurokawa K, et al.: "Current issues and future perspectives of chronic renal failure"J Am Soc Nephrol. (in press).

[文献書誌] Miyata T, et al.: "Progressive mesangial expansion and hypercellularity in transgenic mice of mesangial cell-predominant serpin,megsin"J Clin Invest. (in press).

[文献書誌] Inagi R, et al.: "Efficient detoxification of carbonyl stress by the gloxalase system in peritoneal dialysis"Kidney Int. (in press).

[文献書誌] Miyata T, et al.: "Angiotensine II receptor antagonist and angiotensine converting enzyme(ACE)inhibitor scavenge oxidative radicals and lower the formation of advanced glycation end products"J Am Soc Nephrol. (in press).

[文献書誌] Miyata T, et al.: "Massry and Glassock's Text Book of Nephrology"Alterations in nonenzymatic biochemistry of carbohydrates and lipids in uremia. 1275-1278 (2001)

[文献書誌] Nangaku M, et al.: "Forum Issue of ARS"Relevance of oxidative and carbonyl stress in uremia(in press).

[文献書誌] Miyata T, et al.: "Nutritional Management of Renal Disease"Carbonyl stress in uremia(in press).

2001 年度実績報告書

黒川清東海大学, 医学部, 教授 (30167390)