Minority Predoctoral Fellowship program

少数族裔博士前奖学金计划

• 批准号: 6950364
• 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/6950364
• 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）芘（BaP）是芳烃受体（Ahr）的配体，也是一种强效的基因毒性致癌物。 BaP 的环境暴露与肿瘤发生、动脉粥样硬化和多个器官系统的发育缺陷有关。 Ramos 实验室最近表明，用 BaP 处理后肾培养物与 Ahr 依赖性肾发生破坏有关，肾小球发生和分支形态发生的抑制就证明了这一点。肾发生的特点是间充质到上皮的转变，这个过程受到维尔姆氏肿瘤抑制基因（Wt-1）的调节。 BaP 对肾发生的破坏涉及干扰 Wt-1 剪接和减少 Wt-1 蛋白。本申请提出的研究旨在检验 Ahr 配体通过改变 Wt-1 mRNA 剪接破坏体内肾发生的假设。目标 1 检查子宫内 BaP 暴露对肾发生和 Wt-1 mRNA 剪接的影响。目标 2 将确定 BaP 诱导的肾发生抑制和改变的 Wt-1 剪接变体表达的动力学特征。目标 3 将描述小鼠中肾 M15 细胞系作为模型来评估 -KTS/+KTS mRNA 比率增加的下游影响。