Resolution of Glomerulosclerosis

肾小球硬化症的解决

基本信息

批准号：
8643222
负责人：
AGNES B. FOGO
金额：
$ 33.93万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-02-01 至 2017-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8643222
关键词：
AGTR2 gene Angiotensin II Angiotensin II Type 1 Receptor Blockers Angiotensin-Converting Enzyme Inhibitors Angiotensins Apoptosis Binding Cells Chronic Kidney Failure Cicatrix Cytoskeleton Data Development Dose Epithelial Cells Extracellular Matrix Fibrin Funding Gastric Parietal Cells Glomerular capsule structure Growth Hand Healed Health Human In Vitro Infiltration Injury Intervention Knock-out Knockout Mice Link Location Mediating Modeling Mus Natural regeneration Nephrectomy Parietal Pathway interactions Plasmin Plasminogen Activator Inhibitor 1 Play Proliferating Proteins Proteinuria Renin-Angiotensin System Resolution Role Sclerosis System Testing Time Toxin Urokinase Plasminogen Activator Receptor Vitronectin angiogenesis base blood pressure regulation cell motility constriction diphtheria toxin receptor glomerular function glomerulosclerosis healing in vivo injured injury and repair macrophage migration nephrin novel podocyte prevent promoter public health relevance receptor receptor expression regenerative repaired response restoration stem cell niche tool

项目摘要

DESCRIPTION (provided by applicant): In the previous funding period, we have shown that high doses of angiotensin inhibition, linked to decreased plasminogen activator inhibitor-1 (PAI-1), could regress existing glomerulosclerosis over the short term. This regression was linked to decreased matrix and restoration of plasmin. Our new preliminary data show limited long-term efficacy over six months of this intervention, indicating limitations of blockade of only the AT1 receptor. We postulate that these limits are due to the inability of podocytes to regenerate and proliferate after injury. We therefore will now focus on the potential and mechanisms of podocyte loss and repair to allow optimal regression of existing glomerulosclerosis. Our new exciting preliminary data shows that PAI-1 deficiency protects podocytes after injury with decreased loss and preserved differentiation. Podocytes deficient in PAI-1 revealed remarkable protection with less apoptosis and preserved cytoskeleton in vitro after injury, and systemic PAI-1 knockout mice were protected from development of sclerosis. Based on these exciting new data, our new central hypothesis is that decreased PAI-1 plays a pivotal role in preventing podocyte loss. Novel exciting data implicate the parietal epithelial cell (PECs) as a niche stem cell for podocyte regeneration, and suggest that these PECS could migrate to a visceral epithelial cell location. However, it is not determined whether these migrating parietal cells contribute to repair or alternatively may promote matrix synthesis and sclerosis. We will explore the mechanisms of podocyte protection by PAI-1 deficiency, testing the hypothesis that podocyte PAI-1 deficiency maintains podocyte number and function, and that this is mediated by decrease in the urokinase type plasminogen activator receptor. We will further test the hypothesis that consequences of parietal epithelial cell transition after injury are modulated by PAI-1. We have in hand homozygous floxed mice to allow us to examine in-depth mechanisms of time-specific deletion of PAI-1 in podocytes specifically both in vivo and in vitro. We will tes these hypotheses in a primary podocyte injury model with a toxin receptor specifically expressed only on podocytes (NEP25), and in a model of secondary sclerosis induced by 5/6 nephrectomy. Together, our studies will examine the potential and mechanisms of long-term regression of glomerulosclerosis, hypothesized to be fundamentally linked to PAI-1-dependent mechanisms that decrease podocyte loss and increase podocyte regeneration.

描述（由申请人提供）：在之前的资助期间，我们已经证明，高剂量的血管紧张素抑制与纤溶酶原激活剂抑制剂-1（PAI-1）减少有关，可以在短期内逆转现有的肾小球硬化。这种回归与基质减少和纤溶酶恢复有关。我们的新初步数据显示，这种干预措施在六个月内的长期疗效有限，表明仅阻断 AT1 受体的局限性。我们假设这些限制是由于足细胞在受伤后无法再生和增殖造成的。因此，我们现在将重点关注足细胞丢失和修复的潜力和机制，以实现现有肾小球硬化的最佳消退。我们新的令人兴奋的初步数据表明，PAI-1 缺陷可以在损伤后保护足细胞，减少损失并保留分化。缺乏 PAI-1 的足细胞显示出显着的保护作用，细胞凋亡较少，并且在体外损伤后保留了细胞骨架，系统性 PAI-1 敲除小鼠也免受硬化的发展。基于这些令人兴奋的新数据，我们新的中心假设是 PAI-1 的减少在防止足细胞损失中发挥着关键作用。令人兴奋的新数据表明壁上皮细胞（PEC）是足细胞再生的利基干细胞，并表明这些 PECS 可以迁移到内脏上皮细胞位置。然而，尚不清楚这些迁移的壁细胞是否有助于修复或促进基质合成和硬化。我们将探讨 PAI-1 缺陷对足细胞的保护机制，检验足细胞 PAI-1 缺陷维持足细胞数量和功能的假设，并且这是通过尿激酶型纤溶酶原激活剂受体减少介导的。我们将进一步检验损伤后壁上皮细胞转变的后果受 PAI-1 调节的假设。我们拥有纯合 floxed 小鼠，使我们能够深入研究足细胞中 PAI-1 时间特异性缺失的机制，特别是在体内和体外。我们将在具有仅在足细胞上特异性表达的毒素受体（NEP25）的原发性足细胞损伤模型和由 5/6 肾切除术诱导的继发性硬化模型中测试这些假设。我们的研究将共同探讨肾小球硬化症长期消退的潜力和机制，假设与减少足细胞丢失和增加足细胞再生的 PAI-1 依赖性机制存在根本联系。