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，每年相关的医疗费用估计为 41 亿美元，以足细胞损伤为特征的肾病综合征 (NS) 是其中之一。重要的是，进行性足细胞损伤和丧失也是肾小球疾病进展的关键决定因素，因为足细胞中对损伤调节最关键的信号通路是。目前尚不清楚，迫切需要更好地了解哪些途径最能够调节足细胞损伤和恢复，以便开发出更有针对性和更有效的 NS 疗法。调节 NS 中的足细胞损伤，以开发更有针对性且毒性较小的 NS 疗法。该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 的能力。在此基础上，我们认为对 GR 和 PPARγ 核受体通路和 MAPK 通路以及它们之间的交互作用的特定操作将有助于研究调节足细胞损伤的信号通路，并利用这些知识开发更有效的新疗法。减少 NS 期间的足细胞损伤。拟议研究的基本原理是，对 GR-、PPARγ- 和 MAPK 介导的途径或它们之间的串扰进行特定操作可以改善 NS 中的肾小球损伤，并将促进更多的研究。为了检验我们的假设，我们提出以下具体目标：1) 确定操纵 GR 和 PPARγ 核受体信号传导的关键成分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 介导的信号通路之间串扰的程度和生物学意义，以及 3) 确定操纵 GC、TZD 和 MAPK 介导的信号通路是否可以改善 NS 动物模型中的肾小球损伤。这些研究将确定未来 NS 药物治疗的特定潜在靶点，以及足细胞损伤在其中发挥核心作用的许多其他肾小球疾病，验证这些足细胞信号传导成分作为潜在药物靶点将指导治疗。针对美国最常见的肾脏疾病之一，开发更有针对性、更有效、毒性更小的疗法。