Transcriptional Reprogramming in Podocyte Injury

项目总结： 我们实验室研究的长期目标是开发预防疾病的治疗方法 对儿童和成人足细胞的不可逆转的损害，否则将导致 终末期肾病(ESKD)目前，不可逆转的肾脏损害导致 透析和移植，伴随着相当高的发病率和 死亡率和医疗保健系统每年的花费远远超过200亿美元。我们 假设肾小球疾病进展涉及基因的长期变化 以足细胞为单位的表达式。Wilms‘s Tumor-1基因(WT1)编码一个主要的 调节足细胞基因表达的转录因子。我们最近的研究 证明WT1是足细胞基因表达的主要调节者 似乎调节了维持正常所需的最关键基因的表达 足细胞功能。WT1似乎也调节了其他几个基因的表达 足细胞中重要的转录因子。WT1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Wt1表达 减少受损足细胞，并在基因组水平上定义WT1集合如何 受损足细胞靶基因的变化。我们还确定了第二个 转录因子FOXC2经常与WT1共同作用，调节KEY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 FOXC2在足细胞中的靶基因以及这些基因在受伤后如何变化。这些研究将 在足细胞中识别其活性增加或 损伤后下降，可作为药物干预的靶点。 防止不可逆的足细胞损伤或死亡和随后的肾小球疾病 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.