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Nuclear Receptor and MAP Kinase Signaling in Podocyte Injury

足细胞损伤中的核受体和 MAP 激酶信号转导

基本信息

批准号：
8842627
负责人：
WILLIAM E SMOYER
金额：
$ 32.09万
依托单位：
RESEARCH INST NATIONWIDE CHILDREN'S HOSP
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-01 至 2016-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8842627
关键词：
Adriamycin PFS Agonist Animal Model Animals Area Cells Child Critical Pathways Development Disease Progression Disease remission Dominant-Negative Mutation Drug Targeting End stage renal failure FK506 binding protein 5 Feedback Future Gene Expression Profile Genes Glucocorticoid Receptor Glucocorticoids Goals Health Health Care Costs Injury Kidney Diseases Knowledge Laboratories Leukocytes Literature MAP Kinase Gene MAPK Signaling Pathway Pathway MAPK14 gene MAPK3 gene MAPK8 gene MK-2 Mediating Mitogen-Activated Protein Kinases Molecular Nephrosis Nephrotic Syndrome Nuclear Receptors Pathway interactions Peroxisome Proliferator-Activated Receptors Pharmacotherapy Phosphorylation Play Proteasome Inhibitor Protein Isoforms Proteinuria Publications Reagent Receptor Down-Regulation Receptor Signaling Recovery Regulation Renal glomerular disease Reporting Research Research Personnel Role Signal Pathway Signal Transduction Steroid Resistance Steroids Techniques Testing Thiazolidinediones Validation Work base effective therapy experience in vivo injured member mitogen-activated protein kinase p38 novel novel strategies podocyte protective effect tacrolimus binding protein 4 targeted treatment tool

项目摘要

DESCRIPTION (provided by applicant): Glomerular disease is the third leading cause of end stage renal disease in the US, with its related health care costs estimated at $4.1 billion annually. Nephrotic syndrome (NS), characterized by podocyte injury, is one of the most common forms of glomerular disease. Importantly, progressive podocyte injury and loss are also known to be critical determinants of glomerular disease progression. Since the signaling pathways in podocytes most critical for regulation of injury are not yet known, there is an urgent need to better understand which pathways are most able to regulate podocyte injury and recovery to enable the development of more targeted and effective therapies for NS. Our long-term goal is to define specific molecular signaling pathways able to regulate podocyte injury in NS to develop more targeted and less toxic therapies for NS. The overall objective of this proposal is to determine the ability of the glucocorticoid receptor (GR), peroxisome proliferator-activated receptor γ (PPARγ), and MAPK signaling pathways to regulate podocyte injury, and to exploit this knowledge to develop more effective novel therapies for NS. Based on this, we hypothesize that specific manipulation of the GR and PPARγ nuclear receptor pathways and MAPK pathways, and cross-talk among them, will reduce podocyte injury during NS. The rationale for the proposed studies is that specific manipulation of GR-, PPARγ-, and MAPK-mediated pathways or cross-talk among them can ameliorate glomerular injury in NS, and will enable the development of more effective novel approaches to treat NS in the future. To test our hypothesis, we propose the following Specific Aims: 1) To determine if manipulation of critical components of GR and PPARγ nuclear receptor signaling can enhance podocyte protection from injury, 2) To determine the extent and biologic significance of cross-talk among the GC-, TZD-, and MAPK-mediated signaling pathways during podocyte injury, and 3) To determine if manipulation of GC-, TZD-, and MAPK-mediated signaling can ameliorate glomerular injury in animal models of NS. These studies will identify specific potential targets for future drug therapy in NS, and potentially many other glomerular diseases where podocyte injury plays a central role. Validation of these podocyte signaling components as potential drug targets will guide the development of more targeted, more effective, and less toxic therapies for one of the most common kidney diseases in the US.

描述（由申请人提供）：肾小球疾病是美国终末期肾病的第三大原因，其相关医疗保健费用估计为每年41亿美元。以足细胞损伤为特征的肾病综合征（NS）是最常见的肾小球疾病之一。重要的是，进行性足细胞损伤和丢失也是肾小球疾病进展的关键决定因素。由于对调节损伤最关键的足细胞信号通路尚不清楚，因此迫切需要更好地了解哪些通路最能够调节足细胞损伤和恢复，以开发更有针对性和有效的NS治疗方法。我们的长期目标是确定能够调节NS足细胞损伤的特定分子信号通路，以开发针对NS的更具靶向且毒性更小的治疗方法。本提案的总体目标是确定糖皮质激素受体（GR）、过氧化物酶体增殖物激活受体γ（PPARγ）和MAPK信号通路调节足细胞损伤的能力，并利用这些知识开发更有效的NS新疗法。基于此，我们假设，GR和PPARγ核受体通路和MAPK通路的特异性操作，以及它们之间的相互作用，将减少NS期间足细胞的损伤。这些研究的基本原理是，对GR、PPARγ和MAPK介导的通路或它们之间的相互作用进行特异性操纵可以改善NS中的肾小球损伤，并将使未来能够开发更有效的治疗NS的新方法。为了验证我们的假设，我们提出以下具体目标：1）确定GR和PPARγ核受体信号传导的关键组分的操作是否可以增强足细胞免受损伤的保护，2）确定足细胞损伤期间GC-、TZD-和MAPK-介导的信号传导途径之间的串扰的程度和生物学意义，以及3）确定GC-、TZD-、MAPK-介导的信号传导途径的操作是否可以增强足细胞免受损伤的保护。MAPK介导的信号通路可减轻NS动物模型的肾小球损伤。这些研究将确定特定的潜在目标，为未来的药物治疗NS，并可能在许多其他肾小球疾病，足细胞损伤发挥了核心作用。这些足细胞信号传导成分作为潜在药物靶点的验证将指导针对美国最常见的肾脏疾病之一开发更有针对性，更有效，毒性更低的治疗方法。