Regulation of podocyte function by hic-5

hic-5 对足细胞功能的调节

• 批准号: 8639559
• 负责人: PETER H MUNDEL
• 金额: $ 37.85万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-25 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8639559
• 关键词: Adhesions; Adhesiveness; Adhesives; Apoptosis; Applications Grants; Biological; Biopsy; Cell Death; Cells; Characteristics; Clinic; Complex; Data; Defect; Development; Disease; Disease Progression; ECM receptor; End stage renal failure; Extracellular Matrix; Filtration; Focal Segmental Glomerulosclerosis; Foot Process; Functional disorder; Gene Delivery; Goals; Hypertrophy; Injury; Integrins; Kidney; Kidney Diseases; Left; Maintenance; Mediating; Modeling; Molecular; Mus; Nephrosis; Nephrotic Syndrome; Pathogenesis; Patients; Pattern; Phenotype; Physiological; Play; Process; Proteins; Proteinuria; Publishing; Puromycin Aminonucleoside; Rattus; Receptor, Angiotensin, Type 1; Recovery; Regulation; Renal glomerular disease; Role; Signal Pathway; Stimulus; Structure; Testing; Transgenic Organisms; Up-Regulation; Work; base; cell motility; glomerular basement membrane; mRNA Expression; member; neuronal cell body; novel; overexpression; paxillin; podocyte; protein expression; senescence; slit diaphragm; treatment strategy

DESCRIPTION (provided by applicant): Podocyte foot processes (FPs) and the interposed slit diaphragm (SD) form the final barrier to protein loss, explaining why podocyte injury is typically associated with marked proteinuria. Podocyte dysfunction, represented by FP effacement, disruption of the SD and proteinuria, is often the starting point for progressive kidney disease. Here we propose to test our central hypothesis that the induction of hic-5 expression in podocytes contributes to the pathogenesis of proteinuria by increasing the adhesiveness of podocyte to the extracellular matrix (ECM)/glomerular basement membrane (GBM). We further hypothesize that the persistence of podocyte hic-5 expression in focal segmental glomerulosclerosis (FSGS) confers a senescence phenotype, thereby promoting the progression to ESRD. To test this hypothesis, we propose three Specific Aims. The first Aim will define the molecular mechanism whereby hic-5 increases podocyte adhesion to the ECM, thereby altering cell motility, survival and senescence. Specific Aim two seeks to test whether the induction of podocyte-specific hic-5 expression in mice causes proteinuria. The third Aim will establish whether the prolonged expression of hic-5 in podocytes induces hypertrophy, senescence and apoptosis, thereby causing FSGS and progression to ESRD. If our hypothesis is correct, the work proposed here will have broad significance because it will provide us with a better understanding of the biological mechanism underlying the development of progressive proteinuric kidney diseases and offers a new target for the development of treatment strategies. This should in the long- term enable us to develop novel, podocyte-protective therapies that tackle proteinuric kidney diseases by suppressing the hic-5 mediated increased adhesion of podocytes to the GBM. Such hic-5 blocking compounds may also slow the progression of FSGS to ESRD by inhibiting the hic-5 mediated senescence of podocytes.

描述（由申请人提供）：足细胞足突（FP）和插入的狭缝隔膜（SD）形成蛋白质损失的最后屏障，解释了为什么足细胞损伤通常与明显的蛋白尿相关。足细胞功能障碍，以 FP 消失、SD 破坏和蛋白尿为代表，通常是进行性肾病的起点。在这里，我们建议检验我们的中心假设，即足细胞中 hic-5 表达的诱导通过增加足细胞与细胞外基质 (ECM)/肾小球基底膜 (GBM) 的粘附性来促进蛋白尿的发病机制。我们进一步假设局灶节段性肾小球硬化症 (FSGS) 中足细胞 hic-5 的持续表达赋予衰老表型，从而促进 ESRD 的进展。为了检验这一假设，我们提出了三个具体目标。第一个目标将定义 hic-5 增加足细胞与 ECM 粘附的分子机制，从而改变细胞运动、存活和衰老。具体目标二旨在测试诱导小鼠足细胞特异性 hic-5 表达是否会导致蛋白尿。第三个目标将确定足细胞中 hic-5 的延长表达是否会诱导肥大、衰老和凋亡，从而导致 FSGS 并进展为 ESRD。如果我们的假设正确，那么这里提出的工作将具有广泛的意义，因为它将让我们更好地了解进行性蛋白尿肾病发展的生物学机制，并为制定治疗策略提供新的目标。从长远来看，这应该使我们能够开发出新颖的足细胞保护疗法，通过抑制 hic-5 介导的足细胞与 GBM 粘附的增加来解决蛋白尿肾病。此类 hic-5 阻断化合物还可以通过抑制 hic-5 介导的足细胞衰老来减缓 FSGS 向 ESRD 的进展。