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: 7799051
• 负责人: Jennifer J Schlezinger
• 金额: $ 23.58万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至 2012-09-19
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7799051
• 关键词: 9-deoxy-delta-9-prostaglandin D2; Address; Affect; Agonist; Apoptosis; Aryl Hydrocarbon Receptor; B Cell Proliferation; B-Lymphocytes; Basic Science; Binding; Bone Marrow; Boston; C57BL/6 Mouse; Caspase; Cell Death; Cells; Cessation of life; Chemicals; Collaborations; Complex; Complex Mixtures; Computer Systems Development; DNA Binding; Data; Development; Diabetes Mellitus; Diethylhexyl Phthalate; Drug usage; Environmental Pollution; Esters; Event; Exposure to; Family; Foundations; Goals; Hematopoietic; Hepatocarcinogenesis; Heterodimerization; Immune system; In Vitro; Individual; Inflammatory Response; Insulin; Kidney; Knowledge; MAP Kinase Gene; MAPK14 gene; MAPK8 gene; Maps; Mediating; Mitochondria; Modeling; Molecular; Mono-S; Mus; Nuclear Receptors; Ovarian; PPAR gamma; Pathway interactions; Peroxisome Proliferation; Peroxisome Proliferator-Activated Receptors; Phosphorylation; Phosphotransferases; Placentation; Poison; Positioning Attribute; Pre-B Lymphocyte; RXR; Research Design; Research Project Grants; Signal Pathway; Signal Transduction; Site; Stromal Cells; Superfund; Synthetic Prostaglandins; Techniques; Toxic effect; Tretinoin; United States Environmental Protection Agency; Universities; Work; Xenobiotics; aryl hydrocarbon receptor ligand; base; caspase-8; disease registry; environmental chemical; immunotoxicity; in vivo; lipid biosynthesis; p38 MAPK Signaling Pathway; phthalates; programs; prolyl-proline; response; systems research; transcription factor

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发育的分子机制 系统。我们之前的研究表明，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B淋巴细胞来深刻影响免疫系统的发育 死亡。在定义这种免疫毒性表现的分子机制的过程中，我们 发现原子能机构指定的优先化学品清单中的其他环境化学品 有毒物质和疾病登记，特别是过氧化物酶体增殖物激活受体的激动剂/ (PPARy)，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，可传递有效的死亡信号， 涉及与 AhR 配体激活的细胞内信号传导途径不同的细胞内信号传导途径。此外，一个 内源性骨髓来源的 PPARγ 激动剂、15-脱氧-Al2|I4-前列腺素 J2 或天然存在的 RXRa 激动剂 9-cw-视黄酸可增强对 B 细胞增殖的抑制作用。我们的 PPARy 工作模型 激动剂诱导的死亡基于大量新信息，提出了一条途径： 涉及 caspase、激酶信号级联和 NF-KB 的激活及其之间的相互作用。因此， 提出了三个具体目标： 1. 绘制 PPARy 激动剂诱导的 caspase 依赖性骨髓 B 细胞凋亡图谱 信号通路。 2. 绘制 PPARy 激动剂诱导死亡中激酶激活级联反应并定义其 与 caspase 和 NF-KB 激活的关系。 3. 定义化学协同作用的分子机制 参与 B 细胞凋亡的发生。这些研究不仅有助于我们理解分子效应 PPARy 激动剂对 B 细胞发育的影响，同时也将验证一个易于应用于研究的平台 其他免疫毒性环境化学物质，无论是单独的还是复杂的混合物，在分子水平上。