ZINC FINGERS IN KIDNEY DEVELOPMENT

锌指在肾脏发育中的作用

• 批准号: 2867160
• 负责人: ERIC Grant NEILSON
• 金额: $ 18.09万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-09-30 至 2000-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2867160
• 关键词: animal genetic material tag; developmental genetics; embryo /fetus tissue /cell culture; embryogenesis; gene induction /repression; gene mutation; genetically modified animals; kidney; laboratory mouse; mammalian embryology; nucleic acid sequence; protein structure function; regulatory gene; transcription factor

Metanephric blastema differentiates into kidney following conversion of the nephrogenic cord by migrating ureteric bud epithelium. While various morphologic events in this process have been studied observationally, the molecular and biochemical basis for the prestructural conversion of renal mesenchyme is not known. Studies that address the transdifferentiation of renal stem cells into mature kidney are limited by a lack of known interactions that create signaling pathways. It is quite likely that steps towards terminal differentiation involve changes in protein expression in and around developing nephrons, and such changes are probably controlled by as yet undescribed genes. We hypothesize that the molecular programs determining pattern formation, spatial position, cell fate, phenotype, and structural differentiation are regulated by early sets of master genes responding to morphogenic cues. This hierarchy of genes is probably under the control of transcription factors expressing DNA- binding motifs, and the influence of these proteins over the fate of forming renal tissue is mediated through their linkage to other downstream genes producing organ differentiation. In this application we would like to identify new DNA-binding proteins that play a role in kidney development by their effects on transcription. We believe it is feasible to isolate and characterize several of these early regulatory genes using a favorite gene approach. There is evidence for the importance of zinc finger proteins in the development of nephrons in multiple species from flies forward. We propose to look for other new zinc fingers that are active in embryonic murine kidney. The murine system offers several advantages if one wishes to study higher vertebrates. Most importantly, we expect to determine the phenotype and function of some of these new finger genes by constructing targeted mutations as recombinant mice carrying null alleles, and eventually, by characterizing some of their interactions with other downstream genes. Such information will help establish new positional coordinates for transcriptional pathways in renal growth and maturation.

后肾芽基在转化成肾后分化为肾 输尿管芽上皮迁移形成肾索。 而 研究了这一过程中的各种形态学事件 从观察上看， 肾间质的结构前转化尚不清楚。 的研究 解决肾干细胞向成熟肾的转分化 由于缺乏产生信号的已知相互作用， 途径。 很有可能会走向终点 分化涉及内部及周围蛋白质表达的变化 发育中的肾单位，这种变化可能是由尚未 未描述的基因。 我们假设分子程序 决定模式形成、空间位置、细胞命运、表型， 和结构分化是由早期的几组主 对形态发生线索做出反应的基因 这种基因层次结构 可能是在表达DNA的转录因子的控制下， 结合基序，以及这些蛋白质的命运的影响， 肾组织的形成是通过它们与其他组织的连接来介导的。 产生器官分化的下游基因。 在本申请中，我们希望鉴定新的DNA结合蛋白 在肾脏发育中发挥作用， 转录。 我们相信分离并描述 这些早期的调控基因中的几个使用了一个最喜欢的基因方法。 有证据表明，锌指蛋白的重要性， 从果蝇向前发展的多个物种的肾单位的发展。 我们 我建议寻找其他新的锌指，在胚胎发育中是活跃的。 鼠肾 鼠系统提供了几个优点， 想研究高等脊椎动物 最重要的是，我们希望 确定这些新的手指基因的表型和功能 通过构建靶向突变， 等位基因，并最终，通过描述它们的一些相互作用， 其他下游基因。 这些信息将有助于建立新的 肾脏生长中转录途径的位置坐标， 成熟