Sidekick-1 Upregulation in Podocytes Induces FSGS by Disrupting MAGI-1 Function

足细胞中 Sidekick-1 上调通过破坏 MAGI-1 功能诱导 FSGS

• 批准号: 7695232
• 负责人: Lewis Kaufman
• 金额: $ 33.36万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7695232
• 关键词: Actinin; Adhesions; Adult; Affect; Architecture; BAIAP1 gene; Binding; Biopsy Specimen; Cell Adhesion Molecules; Cells; Data; Defect; Development; Disease; Electrons; End stage renal failure; Focal Segmental Glomerulosclerosis; Functional disorder; Goals; Human; Injury; Kidney; Knockout Mice; Label; Lead; Mediator of activation protein; Microscopic; Modeling; Mus; Nephrosis; Nephrotic Syndrome; Pathogenesis; Pathway interactions; Phenotype; Play; Predisposition; Process; Proteins; Proteinuria; Renal glomerular disease; Reporting; Rodent Model; Role; Staging; Structure; Testing; Time; Transgenic Mice; Transgenic Organisms; United States; Up-Regulation; glomerulosclerosis; mouse model; nephrin; new therapeutic target; novel; novel therapeutics; overexpression; podocyte; public health relevance; slit diaphragm; synaptopodin; therapeutic target

DESCRIPTION (provided by applicant): Focal and segmental glomerulosclerosis (FSGS) is a leading cause of nephrotic syndrome and end-stage renal disease worldwide. Although the mechanisms underlying this important disease are poorly understood, it is clear that the glomerular podocyte plays a central role in disease pathogenesis. In the current proposal, we demonstrate that the homophilic adhesion molecule sidekick-1 (sdk-1) is dramatically upregulated in podocytes in FSGS both in rodent models and in human kidney biopsy samples. We show that sdk-1 strongly interacts with the slit diaphragm linker protein MAGI-1, which is already known to interact with several critical podocyte proteins including synaptopodin, a-actinin-4, nephrin, JAM4, and ¿-catenin. Furthermore, transgenic mice with podocyte-specific overexpression of sdk-1 develop gradual proteinuria, nephrosis, and FSGS. Similarly, MAGI-1 deficient mice also develop gradually progressive proteinuria and FSGS. The similarities between the phenotypes of these two novel mouse models and the fact that the two involved proteins directly interact suggest that similar pathogenic factors may be involved in both models. We hypothesize that the overexpression of sdk-1 in podocytes in FSGS disrupts the ability of MAGI-1 to stabilize podocyte architecture and that over time this leads to the development of glomerular sclerosis. To confirm and identify the involved mechanisms, we propose three specific aims: 1) To determine how the overexpression of sdk-1 affects the binding of MAGI-1 to other critical podocyte proteins. 2) To characterize the renal phenotype of MAGI-1 null mice and to compare it to the phenotype of the podocyte-specific sdk-1 overexpression model. 3) To test the susceptibility of sdk-1 knockout mice to podocyte injury and to the development of FSGS. In this way, we will demonstrate that sdk-1 upregulation is an important factor contributing to the pathogenesis of FSGS and could represent a novel therapeutic target. PUBLIC HEALTH RELEVANCE: Focal and segmental glomerulosclerosis is the leading cause of idiopathic nephrotic syndrome in the United States and the most common cause of end stage renal disease caused by primary glomerular disease worldwide. In this project, we identify a novel mechanism that contributes greatly to the pathogenesis of this important disease and may lead to the identification of novel potential therapeutic targets.

描述（由适用提供）：局灶性和分段性肾小球硬化（FSG）是全球肾病综合征和终末期肾脏疾病的主要原因。尽管对这种重要疾病的基础机制的理解很少，但很明显，肾小球足细胞在疾病发病机理中起着核心作用。在当前的建议中，我们证明了同型粘合分子辅助助剂-1（SDK-1）在啮齿动物模型和人类肾脏活检样品中的FSG中的足细胞中都显着上调。我们表明，SDK-1与缝隙隔膜连接器蛋白MAGI-1强烈相互作用，该蛋白蛋白质MAGI-1与包括突触蛋白，A-Actinin-4，肾素，JAM4和€的几种关键的足细胞蛋白相互作用。此外，具有SDK-1的足细胞特异性过表达的转基因小鼠发育级蛋白尿症，肾脏病和FSG。同样，MAGI-1不足的小鼠也会发展出逐渐进行性蛋白尿症和FSG。这两种新型小鼠模型的表型与两种涉及蛋白质直接相互作用的事实之间的相似性表明，这两个模型都可能涉及相似的致病因素。我们假设FSGS中SDK-1的过表达破坏了MAGI-1稳定足细胞结构的能力，并且随着时间的流逝，这会导致肾小球硬化的发展。为了确认和确定所涉及的机制，我们提出了三个具体目的：1）确定SDK-1的过表达如何影响MAGI-1与其他关键足细胞蛋白的结合。 2）表征MAGI-1 NULL小鼠的肾脏表型，并将其与Podocyte特异性SDK-1过表达模型的表型进行比较。 3）测试SDK-1基因敲除小鼠对足细胞损伤的敏感性和FSG的发展。通过这种方式，我们将证明SDK-1上调是导致FSG发病机理的重要因素，并且可以代表一种新型的治疗靶点。公共卫生相关性：局灶性和节段性的肾小球硬化是美国特发性肾病综合征的主要原因，也是全球原发性肾小球疾病引起的终末期肾脏疾病的最常见原因。在这个项目中，我们确定了一种新的机制，该机制极大地有助于这种重要疾病的发病机理，并可能导致鉴定出新的潜在治疗靶标。