Research Project 4: PPARgamma and Environmental Phthalate-Mediated Toxicity in
研究项目 4:PPARgamma 和邻苯二甲酸盐环境介导的毒性
基本信息
- 批准号:7799051
- 负责人:
- 金额:$ 23.58万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:
- 资助国家:美国
- 起止时间:至 2012-09-19
- 项目状态:已结题
- 来源:
- 关键词:9-deoxy-delta-9-prostaglandin D2AddressAffectAgonistApoptosisAryl Hydrocarbon ReceptorB Cell ProliferationB-LymphocytesBasic ScienceBindingBone MarrowBostonC57BL/6 MouseCaspaseCell DeathCellsCessation of lifeChemicalsCollaborationsComplexComplex MixturesComputer Systems DevelopmentDNA BindingDataDevelopmentDiabetes MellitusDiethylhexyl PhthalateDrug usageEnvironmental PollutionEstersEventExposure toFamilyFoundationsGoalsHematopoieticHepatocarcinogenesisHeterodimerizationImmune systemIn VitroIndividualInflammatory ResponseInsulinKidneyKnowledgeMAP Kinase GeneMAPK14 geneMAPK8 geneMapsMediatingMitochondriaModelingMolecularMono-SMusNuclear ReceptorsOvarianPPAR gammaPathway interactionsPeroxisome ProliferationPeroxisome Proliferator-Activated ReceptorsPhosphorylationPhosphotransferasesPlacentationPoisonPositioning AttributePre-B LymphocyteRXRResearch DesignResearch Project GrantsSignal PathwaySignal TransductionSiteStromal CellsSuperfundSynthetic ProstaglandinsTechniquesToxic effectTretinoinUnited States Environmental Protection AgencyUniversitiesWorkXenobioticsaryl hydrocarbon receptor ligandbasecaspase-8disease registryenvironmental chemicalimmunotoxicityin vivolipid biosynthesisp38 MAPK Signaling Pathwayphthalatesprogramsprolyl-prolineresponsesystems researchtranscription factor
项目摘要
In keeping with the programmatic theme of developmental toxicity, the goal of these studies is to determine
the molecular mechanisms by which environmental chemicals impair the development of the mammalian immune
system. Our previous studies demonstrated that environmentally ubiquitous aryl hydrocarbon receptor (AhR)
agonists profoundly affect immune system development by inducing bone marrow pro- and pro/pre-B lymphocyte
death. In the course of defining the molecular mechanisms through which this immunotoxicity is manifest, we
found that other environmental chemicals included on the list of priority chemicals designated by the Agency for
Toxic Substances and Disease Registry, notably agonists of the peroxisome proliferator activated receptor/
(PPARy) such as di-(2-ethylhexyl) phthalate/ mono-(2-ethylhexyl) phthalate, deliver a potent death signal that
involves intracellular signaling pathways distinct from those activated by AhR ligands. Furthermore, an
endogenous bone marrow-derived PPARy agonist, 15-deoxy-Al2|I4-prostaglandin J2, or a naturally occurring
RXRa agonist, 9-cw-retinoic acid, enhances the inhibition of B cell proliferation. Our working model of PPARy
agonist-induced death, which is based on a considerable foundation of new information, proposes a pathway that
involves the activation of and interaction between caspases, kinase signaling cascades and NF-KB. Accordingly,
three specific aims are proposed: 1. Map PPARy agonist-induced caspase-dependent bone marrow B cell apoptosis
signaling pathways. 2. Map the kinase activation cascade in PPARy agonist-induced death and define its
relationship to caspase and NF-KB activation. 3. Define the molecular mechanisms of chemical synergy resulting
in developing B cell apoptosis. These studies not only will contribute to our understanding of the molecular effects
of PPARy agonists on developing B cells, but also will validate a platform that is easily applicable to the study of
other immunotoxic environmental chemicals, either individually or in complex mixtures, at the molecular level.
为了与发育毒性的纲领性主题保持一致,这些研究的目标是确定
环境化学物质损害哺乳动物免疫系统发育的分子机制
系统我们以前的研究表明,环境中普遍存在的芳烃受体(AhR)
激动剂通过诱导骨髓前B淋巴细胞和前/前B淋巴细胞而深刻地影响免疫系统发育
死亡在确定这种免疫毒性表现的分子机制的过程中,我们
发现其他环境化学品包括在优先化学品名单上指定的机构,
有毒物质和疾病登记处,特别是过氧化物酶体增殖物激活受体激动剂/
例如邻苯二甲酸二-(2-乙基己基)酯/邻苯二甲酸单-(2-乙基己基)酯的PPARy,传递强有力的死亡信号,
涉及不同于AhR配体激活的细胞内信号传导途径。此外,
内源性骨髓源性PPAR γ激动剂,15-脱氧-Al 2| I4-前列腺素J2,或天然存在的
RXR α激动剂9-顺式-视黄酸增强了对B细胞增殖的抑制。我们的PPARy工作模型
激动剂诱导的死亡,这是基于相当基础的新信息,提出了一个途径,
涉及半胱天冬酶、激酶信号级联和NF-κ B的激活和相互作用。因此,委员会认为,
提出了三个具体目标:1。Map PPARy激动剂诱导的半胱天冬酶依赖性骨髓B细胞凋亡
信号通路2.在PPARy激动剂诱导的死亡中绘制激酶激活级联并定义其
与caspase和NF-κ B活化的关系。3.定义化学协同作用的分子机制,
在发展B细胞凋亡中。这些研究不仅将有助于我们理解分子效应
PPARy激动剂对发育中的B细胞的作用,而且还将验证一个容易适用于研究
其他免疫毒性环境化学品,无论是单独或复杂的混合物,在分子水平。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Jennifer J Schlezinger其他文献
Jennifer J Schlezinger的其他文献
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{{ truncateString('Jennifer J Schlezinger', 18)}}的其他基金
Investigating the Perturbation of Bone Health by Per/Polyfluoroalkyl Substances
研究全氟烷基/多氟烷基物质对骨骼健康的干扰
- 批准号:
10589459 - 财政年份:2022
- 资助金额:
$ 23.58万 - 项目类别:
Effects of High Fat Diet and Environmental Obesogen Co-Exposure on Osteoporosis
高脂肪饮食和环境致肥胖因素共同暴露对骨质疏松症的影响
- 批准号:
8258164 - 财政年份:2012
- 资助金额:
$ 23.58万 - 项目类别:
Effects of High Fat Diet and Environmental Obesogen Co-Exposure on Osteoporosis
高脂肪饮食和环境致肥胖因素共同暴露对骨质疏松症的影响
- 批准号:
8538387 - 财政年份:2012
- 资助金额:
$ 23.58万 - 项目类别:
Antagonism of the Ah Receptor in Controlling Breast Cancer Growth and Invasion
Ah 受体在控制乳腺癌生长和侵袭中的拮抗作用
- 批准号:
7738794 - 财政年份:2009
- 资助金额:
$ 23.58万 - 项目类别:
Antagonism of the Ah Receptor in Controlling Breast Cancer Growth and Invasion
Ah 受体在控制乳腺癌生长和侵袭中的拮抗作用
- 批准号:
7847519 - 财政年份:2009
- 资助金额:
$ 23.58万 - 项目类别:
Research Project 4: PPARgamma and Environmental Phthalate-Mediated Toxicity in
研究项目 4:PPARgamma 和邻苯二甲酸盐环境介导的毒性
- 批准号:
6901355 - 财政年份:2005
- 资助金额:
$ 23.58万 - 项目类别:
ARYL HYDROCARBON RECEPTOR AND NF-KAPPAB INTERACTIONS
芳基烃受体和 NF-KAPPAB 相互作用
- 批准号:
6136278 - 财政年份:2000
- 资助金额:
$ 23.58万 - 项目类别:
Research Project 4: PPARgamma and Environmental Phthalate-Mediated Toxicity in
研究项目 4:PPARgamma 和邻苯二甲酸盐环境介导的毒性
- 批准号:
7529665 - 财政年份:
- 资助金额:
$ 23.58万 - 项目类别:
Research Project 4: PPARgamma and Environmental Phthalate-Mediated Toxicity in
研究项目 4:PPARgamma 和邻苯二甲酸盐环境介导的毒性
- 批准号:
7602950 - 财政年份:
- 资助金额:
$ 23.58万 - 项目类别:
Research Project 4: PPARgamma and Environmental Phthalate-Mediated Toxicity in
研究项目 4:PPARgamma 和邻苯二甲酸盐环境介导的毒性
- 批准号:
7529678 - 财政年份:
- 资助金额:
$ 23.58万 - 项目类别:
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