Transcriptional Reprogramming in Podocyte Injury

项目摘要： 我们实验室研究的长期目标是开发治疗方法， 对儿童和成人的足细胞造成不可逆转的损伤，否则会导致 终末期肾病（ESKD）。目前，不可逆的肾损伤导致 透析和移植，伴随着相当大的发病率的情况， 死亡率和医疗保健系统的成本每年超过200亿美元。我们 假设肾小球疾病进展涉及基因的长期变化 在足细胞中表达。Wilms' tumor-1基因（WT 1）编码一种主要的 调节足细胞中基因表达的转录因子。我们最近的研究 表明WT 1是足细胞中基因表达的主要调节因子， 似乎调节维持正常细胞所需的最关键基因的表达， 足细胞功能WT 1似乎也调节其他几种基因的表达。 在足细胞中重要的转录因子。WT 1水平以多种形式降低， 肾小球疾病在这项授权中，我们建议确定为什么Wt 1表达 减少受伤的足细胞，并在基因组水平上定义WT 1 损伤足细胞中靶基因的变化。我们还确定， 转录因子FoxC 2通常与WT 1共同作用，调节转录因子FoxC 2的表达。 足细胞基因我们还将使用全基因组方法来确定一组 足细胞中的FoxC 2靶基因以及这些基因在损伤后如何变化。这些研究将 确定足细胞中的基因和信号通路，其活性增加或 损伤后减少，这可能作为药物干预的目标， 预防不可逆的足细胞损伤或死亡以及随之发生的肾小球疾病， ESKD。

Project Summary: The long-term goal of our laboratory's research is to develop treatments to prevent irreversible damage to podocytes in children and adults, that would otherwise lead to End Stage Kidney Disease (ESKD). At present, irreversible kidney damage leads to dialysis and transplantation, situations that carry with them considerable morbidity and mortality and cost the health care system well over 20 billion dollars annually. We hypothesize that disease progression in glomeruli involves long term changes in gene expression in podocytes. The Wilms' tumor-1 gene (WT1) encodes one of the major transcription factors that regulates gene expression in podocytes. Our recent studies demonstrate that WT1 is a master regulator of gene expression in podocytes and appears to regulate the expression most key genes required to maintain normal podocyte function. WT1 also appears to regulate expression of several of the other transcription factors important in podocytes. WT1 levels decrease in many forms of glomerular disease. In this grant we propose to determine why Wt1 expression decreases in injured podocytes and to define at a genome level how the set of WT1 target genes changes in injured podocytes. We have also determined that a second transcription factor, FoxC2, often acts together with WT1 to regulate expression of key podocyte genes. We will also use a genome-wide approach to determine the set of FoxC2 target genes in podocytes and how these change after injury. These studies will identify genes and signaling pathways in podocytes whose activity increases or decreases after injury, that may serve as targets for pharmacological intervention to prevent irreversible podocyte injury or death and consequent glomerular disease and ESKD.