THE ARYL HYDROCARBON RECEPTOR AND OVARIAN DEVELOPMENT

芳基烃受体与卵巢发育

基本信息

批准号：
6524720
负责人：
REBEKA RAND MERSON
金额：
$ 4.42万
依托单位：
WOODS HOLE OCEANOGRAPHIC INSTITUTION
依托单位国家：
美国
项目类别：
财政年份：
2002
资助国家：
美国
起止时间：
2002-09-25 至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/6524720
关键词：
Osteichthyes apoptosis aromatic hydrocarbon receptor biological signal transduction cell cycle cell type dioxins environmental contamination environmental toxicology histogenesis immunocytochemistry molecular cloning ovary protein protein interaction receptor expression retinoblastoma protein

项目摘要

The aryl hydrocarbon receptor (AHR) is a ligand activated transcription factor that, together with the AHR nuclear translocator (ARNT), binds to dioxin responsive elements (DREs) to regulate gene expression. 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD) is an AHR ligand. TCDD is known to produce a wide variety of physiological and pathological responses, including reproductive dysfunction in vertebrates. The AHR is thought to play a role in the cell cycle, and recent evidence suggests that this may occur through an interaction with the product of the retinoblastoma tumor suppressor gene. The retinoblastoma protein binds transcription factors necessary for cell cycle progression from G1 to S phase. Two distinct regions on the AHR form independent complexes with hypophosphorylated pRB and this interaction is enhanced by AHR ligand binding. The central hypothesis of this study is that the AHR signaling pathway plays an important role in normal ovarian development, and when disrupted by environmental contaminants, oogenesis is altered. Unlike mammalian models, Fundulus express two divergent paralogs of the AHR. These AHRs differ in their tissue specific expression as well as in the putative pRB binding sites. Investigating the functional differences between these receptors in the Fundulus ovary will further define the role of Fundulus AHR1, the mammalian AHR homolog, in cellular physiology. Fundulus populations in areas contaminated with halogenated aromatic hydrocarbons develop heritable resistance to the toxic effects of dioxin. We will approach the central hypothesis that the AHR is important in ovarian development from two perspectives. To test the hypothesis that Fundulus AHR1 and Fundulus AHR2 are functionally distinct in ovarian development we will evaluate expression of the AHRs in ovarian cell types among reproductive stages by immuncytochemistry. Cell specific apoptosis and histopathology will be assessed in TCDD treated dioxin resistant and sensitive Fundulus. Interactions of AHR1 and AHR2 with pRB will be investigated by cloning and characterizing pRB in Fundulus and by the use of in vitro binding assays to assess AHR binding.

芳基碳氢化合物受体（AHR）是配体激活的转录因子，与AHR核转运剂（ARNT）一起，与二恶英反应元件（DRES）结合以调节基因表达。 2、3、7、8-四氯迪本佐-P-二恶英（TCDD）是AHR配体。已知TCDD会产生多种生理和病理反应，包括脊椎动物的生殖功能障碍。 AHR被认为在细胞周期中起作用，最近的证据表明，这可能通过与视网膜细胞瘤抑制基因的乘积发生相互作用而发生。视网膜母细胞瘤蛋白结合了细胞周期从G1到S期所需的转录因子。 AHR上的两个不同区域与下磷酸化的PRB形成独立的复合物，并且通过AHR配体结合增强了这种相互作用。这项研究的核心假设是AHR信号通路在正常的卵巢发育中起着重要作用，当受环境污染物破坏时，卵子发生会改变。与哺乳动物的模型不同，tundulus表达了AHR的两个不同的旁系同源物。这些AHR在组织特异性表达以及推定的PRB结合位点上有所不同。研究这些受体卵巢中这些受体之间的功能差异将进一步定义哺乳动物AHR同源物在细胞生理学中的作用。被卤化芳基碳氢化合物污染的地区的土著种群产生了对二恶英毒性作用的遗传性抗性。我们将采取以下核心假设：AHR从两个角度从卵巢发展中很重要。为了检验卵巢发育功能在功能上与众不同的假设，我们将通过免疫化学评估卵巢细胞类型中AHR的表达。细胞特异性凋亡和组织病理学将在TCDD治疗的二恶英耐药和敏感的眼底地区进行评估。 AHR1和AHR2与PRB的相互作用将通过克隆和表征prb在prindulus中的克隆和表征，并使用体外结合测定法来评估AHR结合。