Function of prostaglandins and histamine in proliferation and differentiation of mast cells.
Function of prostaglandins and histamine in proliferation and differentiation of mast cells.
批准号:
09307052
负责人:
ICHIKAWA Atsushi
金额:
$22.21万
依托单位:
依托单位国家:
日本
项目类别:
Grant-in-Aid for Scientific Research (A)
财政年份:
1997
资助国家:
日本
项目状态:
已结题
起止时间:
1997 至 1999
中文摘要
建立了骨髓源性肥大细胞的原代培养体系,通过检测组氨酸脱羧酶(HDC)、PG合成酶和PG受体的表达来检测组胺和PGs的功能。我们发现,抗原-LGE复合体的刺激增加了COX-2、EP受体、IP和DP受体的表达。此外,我们阐明了HDC的细胞内定位和跨国修饰后的关系;该酶受蛋白酶体降解系统的高度调控。从这些研究中我们发现,组胺和PGs的产生以及PG受体的诱导高度依赖于肥大细胞的分化。这些结果还提示组胺和PGs可能参与肥大细胞的分化特异性过程。基于上述发现,我们利用PG受体缺陷小鼠和HDC缺陷小鼠,研究了PGs和组胺在包括肥大细胞功能在内的不同系统中的生理作用。我们建立了…通过检测每个基因敲除小鼠的表型,发现了更多缺乏每种类型前列腺素受体的ED小鼠,并阐明了前列腺素的生理作用:FP缺陷小鼠由于卵巢中孕酮的持续产生而无法分娩,表明PGF2α在正常分娩所需的黄体溶解中发挥了作用。IP缺陷小鼠血栓形成倾向增加,炎症反应减弱,未见醋酸扭体反应,提示PGI2参与了炎症和痛觉的促进作用。EP3缺陷小鼠对内源性和外源性热原均不表现出发热反应;PGE2通过EP3介导热原诱导的发热产生。EP4基因缺陷小鼠因动脉导管通畅而在出生后3天内死亡。PGE2通过EP4在新生儿动脉导管闭合中起重要作用。EP2基因缺陷的雌性小鼠由于排卵和受精障碍而表现出生育力下降;PGE2通过刺激EP2刺激卵丘扩张和由此导致的cAMP水平增加而促进排卵和受精。通过这些研究,我们证明了受体亚型特异性活性的重要性。HDC基因缺陷小鼠对IgE依赖型L过敏反应减弱,提示组胺在本病中起重要作用。较少
英文摘要
We established primary culture system of bone marrow-derived mast cells, and examined function of histamine and PGs by monitoring expression of histidine decarboxylase(HDC), PG synthetases, and PG receptors. We found that stimulation of antigen-lgE complexes increase expression of COX-2, EP receptors, IP and DP receptors. In addition, we clarified relationship between intracellular localization of HDC and post-transnational modification; this enzyme is highly-regulated by the proteasome degradation system. From these studies, we found that production of histamine and PGs, and induction of PG receptors are highly-regulated dependent on differentiation of mast cells. These results also suggested that histamine and PGs may take part in differentiation-specific processes of mast cells.Based on findings described above, we examined physiological roles of PGs and histamine in various systems including mast cell function by using PG receptor-deficient mice and HDC-deficient mice. We establish … More ed mice deficient in each type of prostanoid receptors, and clarified physiological roles of prostanoids by examining phenotypes in each knockout mice : FP-deficient mice fail to deliver their pups due to persistent production of progesterone in ovaries, indicating that PGF2α plays a role in luteolysis required for normal parturition. IP-deficient mice showed increased tendency of thrombosis, reduced responses of inflammation, and did not show acetic acid-induced writhing responses, indicating that PGI2 participates in promotion of inflammation and pain sensation. EP3-deficent mice did not show febrile responses to both endogenous and exogenous pyrogen; PGE2 mediates pyrogen-induced fever generation via EP3. EP4-deficient mice died within three days after birth due to patency of ductus arteriosus. PGE2 plays an essential role in neonatal closure of ductus arteriosus via EP4. EP2-deficent female mice showed reduced fertility due to impaired ovulation and fertilization; PGE2 contributes to ovulation and fertilization through stimulation of cumulus expansion via EP2 and the resultant increase in cAMP level. Through these studies, we demonstrated importance of receptor subtype-specific activities. HDC-deficient mice showed reduced responses in lgE-dependent type l allergy, indicating that histamine is essential in this disease. Less
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Satoh S.et al.: "The Key Amino Acid Residue of Prostaglandin EP3 Receptor for Governing G Protein Association and Activation Steps"Biochem. Biophys. Res. Commun.. 255. 164-168 (1999)
Satoh S.et al.:“前列腺素 EP3 受体的关键氨基酸残基用于控制 G 蛋白关联和激活步骤”Biochem。
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Tanaka, S., et.al.: "Intrcellular Localization of the 74-and 53-kDa Forms of L-Histidine Decarboxylase in a Rat Basophilic/Mast Cell Line, RBL-2H3"J. Biol. Chem.. 273・14. 8177-8182 (1998)
Tanaka, S., et.al.:“大鼠嗜碱性/肥大细胞系 RBL-2H3 中 74-kDa 和 53-kDa 形式的 L-组氨酸脱羧酶的细胞内定位”J. Biol. 273・14 .8177-8182 (1998)
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Suzuki,S.,et al.: "Membrane targeting and binding of the 74-kDa form of mouse L-histidine decarboxylase via its carboxyl-terminal sequence." FEBS Letters. 437. 44-48 (1998)
Suzuki,S.,et al.:“74-kDa 形式的小鼠 L-组氨酸脱羧酶通过其羧基末端序列进行膜靶向和结合。”
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共 24 条
Mechanisms for adhesion and leakage of pge_2-activated mast cells to and from extracellular matrix
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批准号:17590079
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项目类别:Grant-in-Aid for Scientific Research (C)
-
资助金额:$2.18万
-
财政年份:2005
-
负责人:ICHIKAWA Atsushi
-
依托单位:
A study for role of PGE2 on adhesion of mast cells to fibronectin
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批准号:15390024
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项目类别:Grant-in-Aid for Scientific Research (B)
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资助金额:$9.79万
-
财政年份:2003
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负责人:ICHIKAWA Atsushi
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依托单位:
Biopharmaceutical Research on Prostaglandin Receptors
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批准号:12470496
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项目类别:Grant-in-Aid for Scientific Research (B)
-
资助金额:$10.5万
-
财政年份:2000
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负责人:ICHIKAWA Atsushi
-
依托单位:
Molecular basis of prostanoid receptor-mediated pathogenesis and its drug application
-
批准号:12557211
-
项目类别:Grant-in-Aid for Scientific Research (B)
-
资助金额:$8.51万
-
财政年份:2000
-
负责人:ICHIKAWA Atsushi
-
依托单位:
A study for drug-discovery based on physiological actions of prostanoid receptors
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批准号:10557222
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项目类别:Grant-in-Aid for Scientific Research (B)
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资助金额:$8.64万
-
财政年份:1998
-
负责人:ICHIKAWA Atsushi
-
依托单位:
Analysis of mechanism of functions mediated by receptors of arachodonate cascade
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批准号:07407080
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项目类别:Grant-in-Aid for Scientific Research (A)
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资助金额:$4.22万
-
财政年份:1995
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负责人:ICHIKAWA Atsushi
-
依托单位:
Pharmaceutical approaches using prostanoid receptor knockout mice
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批准号:07557156
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项目类别:Grant-in-Aid for Scientific Research (A)
-
资助金额:$10.11万
-
财政年份:1995
-
负责人:ICHIKAWA Atsushi
-
依托单位:
Structures and Functions of Prostaglandin Receptors
-
批准号:05454568
-
项目类别:Grant-in-Aid for General Scientific Research (B)
-
资助金额:$4.35万
-
财政年份:1993
-
负责人:ICHIKAWA Atsushi
-
依托单位:
A study for gene expression of synthetic enzymes and receptors for lipid biofactors
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批准号:05304027
-
项目类别:Grant-in-Aid for Co-operative Research (A)
-
资助金额:$19.97万
-
财政年份:1993
-
负责人:ICHIKAWA Atsushi
-
依托单位:
New assay systems for the development of inhibitory drugs against activated mast cell function
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批准号:04557108
-
项目类别:Grant-in-Aid for Developmental Scientific Research (B)
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资助金额:$11.39万
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财政年份:1992
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负责人:ICHIKAWA Atsushi
-
依托单位:
Bio-pharmacological study for the action of bioactive molecules which control the reciprocal relationship between mast cells and other inflammatory cells
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批准号:02404079
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项目类别:Grant-in-Aid for General Scientific Research (A)
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资助金额:$14.91万
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财政年份:1990
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负责人:ICHIKAWA Atsushi
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依托单位:
Signal Transduction and Arachidonic Acid Metabolism in the Aid Drug of Development
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批准号:01304049
-
项目类别:Grant-in-Aid for Co-operative Research (A)
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资助金额:$6.91万
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财政年份:1989
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负责人:ICHIKAWA Atsushi
-
依托单位:
Multifunction of mast cells in inflammation tissue
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批准号:62480421
-
项目类别:Grant-in-Aid for General Scientific Research (B)
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资助金额:$4.16万
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财政年份:1987
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负责人:ICHIKAWA Atsushi
-
依托单位:
A Research for the Development of Antiallergic-Drug with using Growing Differentiated Mast Cells in Culture System
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批准号:60480461
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项目类别:Grant-in-Aid for General Scientific Research (B)
-
资助金额:$4.1万
-
财政年份:1985
-
负责人:ICHIKAWA Atsushi
-
依托单位:
国内基金
海外基金
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