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：
8694019
负责人：
WILLIAM E SMOYER
金额：
$ 32.08万
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 2018-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8694019
关键词：
2,4-thiazolidinedione 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 PPAR Pathway 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 public health relevance tacrolimus binding protein 4 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 g (PPARg), 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 PPARg 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-, PPARg-, 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 PPARg 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）：肾小球疾病是美国末期肾脏疾病的第三主要原因，其相关医疗保健费用估计为41亿美元。以足细胞损伤为特征的肾病综合征（NS）是肾小球疾病的最常见形式之一。重要的是，众所周知，进行性足细胞损伤和丧失是肾小球疾病进展的关键决定因素。由于尚不清楚对损伤调节最重要的足细胞中的信号传导途径，因此迫切需要更好地了解哪些途径最能够调节足细胞损伤并恢复以使NS开发更有针对性且有效的疗法。我们的长期目标是定义能够调节NS中足细胞损伤的特定分子信号传导途径，以开发出对NS的靶向和毒性较小的疗法。该提案的总体目的是确定糖皮质激素受体（GR），过氧化物酶体增殖物激活的受体G（PPARG）和MAPK信号通路调节Podocyte损伤的能力，并利用这种知识来为NS开发更有效的新颖疗法。基于这一点，我们假设对GR和PPARG核受体途径和MAPK途径的特定操纵以及其中的跨对词将减少NS期间的足细胞损伤。提出的研究的基本原理是，对GR-，PPARG和MAPK介导的途径的特定操纵或它们中的串扰可以改善NS中的肾小球损伤，并将能够开发出更有效的新颖方法来治疗NS的NS。为了检验我们的假设，我们提出以下具体目的：1）确定对GR和PPARG核受体信号的关键组件的操纵是否可以增强受伤的足细胞保护，2）确定跨与gc，tzd-和mapk介导的在podocyte期间的gc-，tzd-和mapk介导的信号通道的程度和生物学意义，以确定podocyte in-podocip，以及是否确定podococyte和3），以确定是否在podcy the and podocip podocip，以及是否确定了是否是否在podcy podocyte和3）中确定是否是否在podip path path。 MAPK介导的信号传导可以改善NS动物模型的肾小球损伤。这些研究将确定未来药物治疗的特定潜在靶标在NS中，以及许多其他肾小球疾病的肾小球疾病起着核心作用。这些足细胞信号成分作为潜在药物靶标的验证将指导美国最常见的肾脏疾病之一的更有针对性，更有效，更毒性的疗法。