The role of dendrin in glomerular disease progression

树突蛋白在肾小球疾病进展中的作用

• 批准号: 8963906
• 负责人: Kirk N Campbell
• 金额: $ 38.14万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-10 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8963906
• 关键词: Accounting; Address; Affect; Apoptotic; Architecture; Binding; Biological; Cell Nucleus; Cell Survival; Cells; Clinical; Cytoplasm; Data; Deposition; Development; Disease; Disease Progression; End stage renal failure; Fibronectins; Focal Segmental Glomerulosclerosis; Gene Deletion; Goals; Human; In Vitro; Injury; Kidney; Knowledge; Mediating; Mediator of activation protein; Modeling; Molecular; Mus; Nuclear; Nuclear Translocation; Outcome; Pathogenesis; Pathway interactions; Pharmaceutical Preparations; Phosphorylation; Physiological; Process; Protein Inhibition; Protein Isoforms; Proteins; Proteomics; Renal glomerular disease; Research; Role; Signal Pathway; Signal Transduction; Signaling Molecule; Steroid Resistance; System; Technology; Testing; Therapeutic; Therapeutic Agents; Therapeutic Intervention; Transcription Factor AP-1; Transgenic Mice; Transgenic Organisms; Work; base; cell injury; cost; dendrin; genetic variant; glomerulosclerosis; improved; in vivo; inhibitor/antagonist; innovation; mesangial cell; mouse model; mutant; new therapeutic target; novel; novel therapeutics; podocyte; public health relevance; therapeutic target

 DESCRIPTION (provided by applicant): A critical barrier to the identification of appropriate therapeutic targets to treat glomerular disease is the limited understanding of signaling cascades that regulate podocyte injury and renal survival. Our long term goal is to enhance the pipeline of putative therapeutic targets available to tackle human glomerular disease by elucidating the details and functional significance of key signaling pathways that regulate podocyte injury and survival. Our preliminary data have identified dendrin as a key pro injury signaling molecule that promotes podocyte depletion and is involved in podocyte mesangial cell crosstalk. We have identified human dendrin gene variants that segregate with familial steroid resistant focal segmental glomerulosclerosis (FSGS) and identified the pro survival Hippo pathway effector Yes associated protein (YAP) as an inhibitor of dendrin function. The overall objective of this application is to define the role of dendrin as a key mediator of pathogenic podocyte mesangial cell crosstalk and subsequent glomerular disease progression.Our central hypothesis is that dendrin is regulated in a phosphorylation dependent manner by YAP, where disease associated dendrin mutants may induce podocyte injury though decreased YAP inhibition. Dendrin regulated soluble factors from podocytes promote mesangial cell fibronectin secretion, leading to mesangial matrix expansion and glomerular disease progression. The rationale for the proposed research is that defining how dendrin function is inhibited by YAP and characterizing its role in glomerular disease progression will advance understanding of glomerular disease progression as well as the quest for novel therapeutic targets available for clinical use. Our hypothesis will be tested by pursuing two specific aims: Aim 1 will explore the inhibition of wild type and FSGS associated dendrin mutants by YAP. We will define the molecular interaction between phosphorylated YAP and the dendrin isoforms and characterize the consequences of binding in the context of cell survival and dendrin subcellular localization and function. We will also test in vivo whether transgenic expression of YAP in podocytes slows murine glomerular disease progression by inhibiting dendrin function. In Aim 2 we will define the role of dendrin in pathogenic podocyte mesangial cell crosstalk using our novel established in vitro cell systems as well as an inducible transgenic mouse model of crosstalk. Our innovative approach utilizes state of the art proteomics technology to identify dendrin regulated soluble factors from podocytes that induce mesangial cell fibronectin secretion. These contributions are significant because they represent the first step in a continuum of research that is expected to advance understanding of glomerular disease progression and identify therapeutic targets and strategies to improve clinical outcomes.

 描述（由申请人提供）：识别治疗肾小球疾病的适当治疗靶点的一个关键障碍是对调节足细胞损伤和肾脏存活的信号级联反应的有限了解。我们的长期目标是增强可用的假定治疗靶点的管道。通过阐明调节足细胞损伤和存活的关键信号通路的细节和功能意义来解决人类肾小球疾病。我们的初步数据已确定树突蛋白是促进足细胞的关键促损伤信号分子。我们已经鉴定出与家族性类固醇抵抗性局灶节段性肾小球硬化症 (FSGS) 分离的人树突蛋白基因变异，并鉴定了促生存 Hippo 通路效应子 Yes 相关蛋白 (YAP) 作为树突蛋白功能的抑制剂。本申请的总体目标是确定树突蛋白作为致病性足细胞系膜细胞串扰和随后的肾小球疾病的关键介质的作用我们的中心假设是，树突蛋白以磷酸化依赖性方式受到 YAP 的调节，其中与疾病相关的树突蛋白突变体可能通过减少 YAP 抑制来诱导足细胞损伤，从而促进系膜细胞纤连蛋白的分泌，导致系膜基质扩张和生长。拟议研究的基本原理是确定 YAP 如何抑制树突蛋白功能并描述其在肾小球疾病中的作用。进展将促进对肾小球疾病进展的理解以及对可用于临床的新治疗靶点的探索。我们的假设将通过追求两个具体目标进行检验：目标 1 将探索 YAP 对野生型和 FSGS 相关树突蛋白突变体的抑制作用。我们将定义磷酸化 YAP 和树突蛋白亚型之间的分子相互作用，并表征结合在细胞存活和树突蛋白亚细胞定位和功能方面的后果。我们还将测试体内是否转基因表达。足细胞中的 YAP 通过抑制树突蛋白功能来减缓小鼠肾小球疾病的进展。在目标 2 中，我们将使用我们新建立的体外细胞系统以及可诱导的转基因小鼠模型来确定树突蛋白在致病性足细胞系膜细胞串扰中的作用。最先进的蛋白质组学技术，可从诱导系膜细胞纤连蛋白分泌的足细胞中识别树突蛋白调节的可溶性因子。这些研究意义重大，因为它们代表了一系列研究的第一步，这些研究有望增进对肾小球疾病进展的了解并确定治疗靶点和策略以改善临床结果。