Transcriptional Reprogramming in Podocyte Injury

足细胞损伤中的转录重编程

• 批准号: 9149798
• 负责人: Jordan A Kreidberg
• 金额: $ 44.76万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-03 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9149798
• 关键词: Adriamycin PFS; Adult; Binding; Biology; Cell Adhesion; Cessation of life; ChIP-seq; Child; Chronic Kidney Failure; Complex; Cytoskeletal Modeling; Development; Dialysis procedure; Disease; Disease Progression; End stage renal failure; Epigenetic Process; Focal Segmental Glomerulosclerosis; Gene Expression; Gene Expression Profile; Gene Expression Regulation; Gene Proteins; Gene Silencing; Gene Targeting; Genes; Genetic; Genome; Genomics; Goals; Grant; Healthcare Systems; Human; Injury; Intervention; Kidney; Kidney Diseases; Laboratory Research; Lead; Maintenance; Molecular; Morbidity - disease rate; Nephrotic Syndrome; Ontology; Process; Proteins; Regulation; Regulator Genes; Renal function; Renal glomerular disease; Signal Transduction; Signaling Protein; Site; System; Transplantation; WT1 gene; base; cell type; cost; genome-wide; genome-wide analysis; glomerular filtration; injured; mortality; novel; podocyte; prevent; repaired; slit diaphragm; therapeutic target; transcription factor

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.

项目概要： 我们实验室研究的长期目标是开发治疗方法来预防 对儿童和成人的足细胞造成不可逆转的损害，否则会导致 终末期肾病（ESKD）。目前，不可逆的肾脏损害导致 透析和移植，以及伴随着相当大的发病率的情况和 每年造成的死亡和医疗保健系统的费用远远超过 200 亿美元。我们 假设肾小球疾病进展涉及基因的长期变化 足细胞中的表达。 Wilms 肿瘤 1 基因 (WT1) 编码一种主要的 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因子 似乎调节维持正常所需的最关键基因的表达 足细胞功能。 WT1 似乎还调节其他几种基因的表达 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。在这笔资助中，我们建议确定为什么 Wt1 表达 减少受伤的足细胞，并在基因组水平上定义 WT1 组如何 受损足细胞中的靶基因变化。我们还确定了第二个 转录因子 FoxC2 通常与 WT1 一起作用，调节关键蛋白的表达 足细胞基因。我们还将使用全基因组方法来确定一组 FoxC2 足细胞中的靶基因以及这些基因在损伤后如何变化。这些研究将 识别足细胞中活性增加或的基因和信号通路 损伤后下降，这可以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而来的肾小球疾病和 ESKD。