MOLECULAR MECHANISM OF IMMUNOTOXIC ACTION OF TCDD & DTT
MOLECULAR MECHANISM OF IMMUNOTOXIC ACTION OF TCDD & DTT
批准号:
3252924
负责人:
FUSAO HIRATA
金额:
$15.41万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
1989
资助国家:
美国
项目状态:
已结题
起止时间:
1989-02-01 至 1994-01-31
关键词:
arachidonate autoradiography binding proteins complementary DNA dioxins dithiol environmental toxicology enzyme inhibitors fatty acid metabolism fluorescence microscopy gel electrophoresis gene expression genetic regulation halobiphenyl /halotriphenyl compound high performance liquid chromatography histocompatibility antigens hormone receptor human subject immunoregulation immunotoxicity interleukin 1 laboratory mouse macrophage monocyte nucleic acid hybridization nucleic acid probes protein biosynthesis radioimmunoassay receptor binding second messengers steroids tissue /cell culture tumor necrosis factor alpha
中文摘要
一些环境污染物,如2.3.7.8
四氯二苯并双恶英和1.1.1-三氯-2-(2-
氯苯基)-2-(4-氯苯基)乙烷(o,p‘DTT)已知具有
类固醇作用和免疫毒性作用在动物和
人类。这些化合物与细胞内受体蛋白结合。
与糖皮质激素和雌激素的作用相似。自.以来
免疫系统在宿主抵抗中起着至关重要的作用
动态平衡,外源生物诱导的免疫调节可能
是对健康产生负面影响的基础。单核/巨噬细胞
在启动免疫调节方面有各种关键功能,
通过抗原提呈、单核细胞因子产生和
形成花生四烯酸代谢物,这些功能是
已知受到糖皮质激素和雌激素的影响。在
在这里提出的项目,我们的目标是研究分子
类固醇和外源物质对血管内皮细胞功能的作用机制
单核/巨噬细胞和随后的细胞免疫。
具体目的是检查(A)这些外来生物和
类固醇与相同或不同的受体结合,(B)无论它们是
诱导或阻断第二信使蛋白的合成
类固醇,(C)它们对IL的基因表达有什么作用
1、肿瘤坏死因子、人类白细胞抗原-DR和脂皮质素,以及(D)这些对IL的影响
1、肿瘤坏死因子、人类白细胞抗原-DR和脂皮质蛋白的改变归因于
花生四烯酸代谢或异种生物基因调控-
受体复合体或两者兼而有之。外源生物和类固醇将是
与分离的人外周血体外孵育
单核细胞/巨噬细胞在缺乏和存在特异性和
非特异性激活剂,如伽马-LFN、脂多糖和佛波酯。
花生四烯酸代谢产物的高效液相色谱定量分析
高效液相色谱。约束性分析将是
通过竞争性配基结合分析进行。身份识别
新诱导的蛋白质将以二维方式进行
~(35)S蛋氨酸的电泳法及其生物学作用
对单核细胞和T淋巴细胞进行检测。这项规定
白介素1、肿瘤坏死因子、脂皮质素(推测为第二信使
糖皮质激素)和人类白细胞抗原-DR基因的表达将被研究
Northern Blot以它们的cDNA克隆为探针。利用
外源生物免疫毒性机制的研究进展
免疫调节导致免疫抑制的机制
(获得性免疫缺陷),我们建议建立机制
外源物质对生物化学和细胞功能作用的研究
单核/巨噬细胞。
英文摘要
Some environmental contaminants such as 2.3.7.8
tetrachlorodibenzoparadioxin (TCDD) and 1.1.1-trichloro-2-(2-
chlorophenyl)-2-(4-chlorophenyl)ethane (o,p'DTT), are known to have
steroidal actions as well as immunotoxic actions in animals and
humans. These compounds bind to intracellular receptor proteins
similar to those for glucocorticoids and estrogens. Since the
immune system plays a crucial role in host resistance and
homeostasis, the immunomodulation induced by the xenobiotics may
be the basis for adversed health effects. Monocytes/macrophages
have various key functions in initiating the immune regulation,
mediating through antigen presentation, monokine production, and
formation of arachidonate metabolites, and these functions are
known to be affected by glucocorticoids and estrogens. In the
projects proposed herein, we aim to investigate the molecular
mechanism of actions of steroids and xenobiotics on function of
monocytes/macrophages and subsequently, of cell mediated immunity.
The specific aims are to examine (a) whether these xenobiotics and
steroids bind to the same or different receptors, (b) whether they
induce or block the synthesis of second messenger proteins of
steroids, (c) what are their actions on the gene expression of IL
1, TNF, HLA-DR and lipocortin and (d) whether these effects on IL
1, TNF, HLA-DR and lipocortin are attributed to alteration of
arachidonate metabolism or of gene regulation by the xenobiotic-
receptor complex or both. Xenobiotics and steroids will be
incubated in vitro with fractionated human peripheral
monocytes/macrophages in the absence and presence of specific and
nonspecific activators such as gamma-lFN, LPS and phorbol esters.
Metabolites of arachidonate will be quantitatively analyzed by high
performance liquid chromatography. The binding analysis will be
performed by competitive ligand binding assays. Identification of
newly induced proteins will be carried out by two dimensional
electrophoresis using (35S)methionine and their biological actions
on monocytes and T lymphocytes will be examined. The regulation
of IL 1, TNF, lipocortin (putative second messenger of
glucocorticoids) and HLA-DR gene expression will be investigated
by the Northern Blot using their cDNA clones as probes. To exploit
not only the mechanism of immunotoxicity of xenobiotics but also
the mechanism of immunoregulation leading to the immunosuppression
(acquired immune deficiency), we propose to establish the mechanism
of action of xenobiotics on the biochemical and cellular functions
of monocytes/macrophages.
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Biology of phospholipase inhibitory proteins.
磷脂酶抑制蛋白的生物学。
DOI:
10.1007/978-1-4613-0651-1_14
发表时间:
1990
期刊:
Advances in experimental medicine and biology
影响因子:
--
作者:
[Hirata,F, Hirata,A]
通讯作者:
Hirata,A
Multiple mechanisms of bronchoconstrictive responses to endothelin-1.
对内皮素 1 的支气管收缩反应的多种机制。
DOI:
10.1097/00005344-199100177-00061
发表时间:
1991
期刊:
Journal of cardiovascular pharmacology
影响因子:
3
作者:
[Nomura,A, Ninomiya,H, Saotome,M, Ohse,H, Ishii,Y, Uchida,Y, Hirata,F, Hasegawa,S]
通讯作者:
Hasegawa,S
IL-1 beta regulates the expression of the Gi2 alpha gene via lipid mediators in guinea pig tracheal muscle.
IL-1 beta 通过豚鼠气管肌肉中的脂质介质调节 Gi2 α 基因的表达。
DOI:
10.1006/bbrc.1994.2408
发表时间:
1994
期刊:
Biochemical and biophysical research communications
影响因子:
3.1
作者:
[Hirata,F, Lee,JY, Sakamoto,T, Nomura,A, Uchida,Y, Hirata,A, Hasegawa,S]
通讯作者:
Hasegawa,S
Endothelins constrict guinea pig tracheas by multiple mechanisms.
内皮素通过多种机制收缩豚鼠气管。
DOI:
--
发表时间:
1992
期刊:
The Journal of pharmacology and experimental therapeutics
影响因子:
--
作者:
[Ninomiya,H, Uchida,Y, Saotome,M, Nomura,A, Ohse,H, Matsumoto,H, Hirata,F, Hasegawa,S]
通讯作者:
Hasegawa,S
ET-1 released histamine from guinea pig pulmonary but not peritoneal mast cells.
ET-1从豚鼠肺部释放组胺,但不从腹膜肥大细胞释放组胺。
DOI:
10.1016/0006-291x(92)92331-q
发表时间:
1992
期刊:
Biochemical and biophysical research communications
影响因子:
3.1
作者:
[Uchida,Y, Ninomiya,H, Sakamoto,T, Lee,JY, Endo,T, Nomura,A, Hasegawa,S, Hirata,F]
通讯作者:
Hirata,F
共 11 条
LIPOCORTINS (ANNEXINS) AND METAL-INDUCED MUTAGENESIS
-
批准号:6635519
-
项目类别:
-
资助金额:$28.58万
-
财政年份:2001
-
负责人:FUSAO HIRATA
-
依托单位:
LIPOCORTINS (ANNEXINS) AND METAL-INDUCED MUTAGENESIS
-
批准号:6518202
-
项目类别:
-
资助金额:$28.58万
-
财政年份:2001
-
负责人:FUSAO HIRATA
-
依托单位:
LIPOCORTINS (ANNEXINS) AND METAL-INDUCED MUTAGENESIS
-
批准号:6224884
-
项目类别:
-
资助金额:$28.09万
-
财政年份:2001
-
负责人:FUSAO HIRATA
-
依托单位:
MOLECULAR MECHANISM OF IMMUNOTOXIC ACTION OF TCDD & DTT
-
批准号:3252921
-
项目类别:
-
资助金额:$2.03万
-
财政年份:1989
-
负责人:FUSAO HIRATA
-
依托单位:
MOLECULAR MECHANISM OF IMMUNOTOXIC ACTION OF TCDD & DTT
-
批准号:3252922
-
项目类别:
-
资助金额:$15.93万
-
财政年份:1989
-
负责人:FUSAO HIRATA
-
依托单位:
MOLECULAR MECHANISM OF IMMUNOTOXIC ACTION OF TCDD & DTT
-
批准号:3252923
-
项目类别:
-
资助金额:$17.33万
-
财政年份:1989
-
负责人:FUSAO HIRATA
-
依托单位:
MOLECULAR MECHANISM OF IMMUNOTOXIC ACTION OF TCDD & DTT
-
批准号:3252919
-
项目类别:
-
资助金额:$20.73万
-
财政年份:1989
-
负责人:FUSAO HIRATA
-
依托单位:
MOLECULAR MECHANISM OF IMMUNOTOXIC ACTION OF TCDD & DDT
-
批准号:2153765
-
项目类别:
-
资助金额:$16.99万
-
财政年份:1989
-
负责人:FUSAO HIRATA
-
依托单位:
RECEPTOR-EFFECTOR COUPLING OF SEROTONIN RECEPTORS
-
批准号:3409390
-
项目类别:
-
资助金额:$11.34万
-
财政年份:1987
-
负责人:FUSAO HIRATA
-
依托单位:
海外基金