Minority Predoctoral Fellowship program

少数族裔博士前奖学金计划

• 批准号: 6829760
• 负责人: ADRIAN NANEZ
• 金额: $ 3.81万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-01 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6829760
• 关键词: RNA splicing; SDS polyacrylamide gel electrophoresis; Wilms' tumor; aromatic hydrocarbon receptor; benzopyrenes; biological models; cell differentiation; embryo /fetus; gene expression; gene induction /repression; gene targeting; genetic transcription; genetically modified animals; kidney; laboratory mouse; ligands; messenger RNA; nephrogenesis; nucleic acid purification; organ culture; predoctoral investigator; protein purification; renal glomerulus; transfection /expression vector; tumor suppressor genes

DESCRIPTION (provided by applicant): Benzo(a)pyrene (BaP) is a ligand for the aryl hydrocarbon receptor (Ahr) and a potent genotoxic carcinogen. Environmental exposure to BaP has been associated with tumorigenesis, atherosclerosis and developmental deficits in several organ systems. The Ramos laboratory has recently shown that treatment of metanephric cultures with BaP is associated with Ahr-dependent disruption of nephrogenesis, as evidenced by inhibition of glomerulogenesis and branching morphogenesis. Nephrogenesis is characterized by mesenchymal-to-epithelial transition and this process is regulated by the Wilm's tumor suppressor gene (Wt-1). Disruption of nephrogenesis by BaP involves interference with Wt-1 splicing and reductions in Wt-1 protein. Studies are proposed in this application to test the hypothesis that ligands of Ahr disrupt nephrogenesis in vivo by altering Wt-1 mRNA splicing. Aim 1 examines the impact of in utero BaP exposure on nephrogenesis and Wt-1 mRNA splicing. Aim 2 will determine the kinetic profiles of BaP-induced inhibition of nephrogenesis and altered Wt-1 splice variant expression. Aim 3 will characterize the mouse mesonephric M15 cell line as a model to evaluate downstream effects of increased -KTS/+KTS mRNA ratios.

描述（由申请人提供）：苯并（a）pyrene（BAP）是芳基烃受体（AHR）和有效的遗传毒性致癌物的配体。在几种器官系统中，环境暴露于BAP与肿瘤发生，动脉粥样硬化和发育缺陷有关。 Ramos实验室最近表明，用BAP的替代培养物的治疗与AHR依赖性肾脏发生的破坏有关，这可以通过抑制肾小球发生和分支形态发生的抑制证明。肾脏发生的特征是间充质到上皮过渡，该过程受Wilm肿瘤抑制基因（WT-1）的调节。通过BAP破坏肾脏的破坏涉及干扰WT-1剪接和WT-1蛋白质中的减少。在此应用中提出了研究，以检验以下假设：AHR的配体通过改变WT-1 mRNA剪接来破坏体内的肾病。 AIM 1检查了子宫BAP暴露对肾脏发生和WT-1 mRNA剪接的影响。 AIM 2将确定BAP诱导的肾脏发生抑制和WT-1剪接变体表达的动力学谱。 AIM 3将表征小鼠中肾M15细胞系作为评估增加-kts/+kts mRNA比的下游效应的模型。