Nuclear Receptor and MAP Kinase Signaling in Podocyte Injury

描述（由申请人提供）：肾小球疾病是美国终末期肾脏疾病的第三大原因，其相关医疗费用估计每年为41亿美元。以足细胞损伤为特征的肾病综合征（NS）是肾小球疾病中最常见的一种。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。由于足细胞中对损伤调节最关键的信号通路尚不清楚，因此迫切需要更好地了解哪些通路最能调节足细胞损伤和恢复，以便开发更有针对性和更有效的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，以开发更具针对性和毒性更低的NS治疗方法。本研究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g （PPARg）和MAPK信号通路调节足细胞损伤的能力，并利用这一知识开发更有效的NS新疗法。基于此，我们假设特异性地操纵GR和PPARg核受体通路和MAPK通路，以及它们之间的相互作用，可以减轻NS期间足细胞的损伤。这些研究的基本原理是，特异性操纵GR-、ppar -和mapk介导的通路或它们之间的串扰可以改善NS的肾小球损伤，并将使未来开发更有效的治疗NS的新方法成为可能。为了验证我们的假设，我们提出以下具体目的：1)确定操纵GR和ppar核受体信号的关键成分是否可以增强足细胞对损伤的保护；2)确定GC-、TZD-和mapk介导的信号通路在足细胞损伤过程中的串扰程度和生物学意义；3)确定GC-、TZD-和mapk介导的信号通路的操纵是否可以改善NS动物模型中的肾小球损伤。这些研究将确定未来药物治疗的特定潜在靶点

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.