Mechanisms and Selective Modulation of PPARy for the Treatment of Podocytopathies

PPARy 治疗足细胞病的机制和选择性调节

基本信息

批准号：
10660400
负责人：
Shipra Agrawal
金额：
$ 25.03万
依托单位：
STATE UNIVERSITY NEW YORK STONY BROOK
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-06-15 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10660400
关键词：
ATAC-seq Adipocytes Adverse effects Agonist Albumins Animal Model Antidiabetic Drugs Binding Cardiovascular Diseases ChIP-seq Chronic Kidney Failure Clinical Clinical Trials Cytoskeleton Data Development Diabetes Mellitus Disease Disease Progression Drug Kinetics Economic Burden End stage renal failure Event Filtration Functional disorder Genes Genetic Transcription Goals Health Human Hypertension Injury Kidney Diseases Knowledge Lipids Mediating Medical Messenger RNA Modeling Molecular Nephrotic Syndrome Nuclear Receptors Oligonucleotides Outcome PPAR gamma PTGS2 gene Pathway interactions Peroxisome Proliferator-Activated Receptors Pharmacodynamics Pioglitazone Plasminogen Activator Inhibitor 1 Poly A Polyadenylation Proteinuria Public Health Publishing RNA Splicing Rattus Refractory Regulation Renal glomerular disease Reporting Repression Role Signal Transduction Site Structure Testing Therapeutic Thiazolidinediones Toxic effect Toxin Transactivation Transcriptional Regulation Treatment Cost Variant WT1 gene clinical application comorbidity effective therapy efficacy evaluation improved lead series lipid biosynthesis mortality next generation novel novel strategies podocyte posttranscriptional pre-clinical protective effect side effect slit diaphragm targeted treatment transcriptomics

项目摘要

ABSTRACT / PROJECT SUMMARY Glomerular disease manifests as nephrotic syndrome with high-grade proteinuria with co-morbidities, and is characterized by podocyte injury and loss, which are critical determinants of disease progression. Glomerular disease can unfortunately be frequently refractory to current treatments, leading to progression to chronic kidney disease and end-stage kidney disease. Thus, there is an unmet medical need to identify more effective and less toxic podocyte-targeted treatments for glomerular disease. We have previously demonstrated that PPARγ agonists and thiazolidinediones such as pioglitazone, protect podocytes from injury, reduce proteinuria and glomerular injury in an animal model of glomerular disease, and improve clinical outcomes in nephrotic syndrome. Despite these advances, lack of their podocyte-specific mechanistic understanding and unwanted side effects has impeded their robust clinical application. Their widespread use as anti-diabetic drugs has also been under scrutiny, which has however led to the emergence of more selective modulators of PPARγ which have shown promise in recent clinical trials (NCT02638038). Motivated by these developments and to enable the clinical application of PPARγ modulation, here we seek to move away from traditional agonists and toward selective modulation of PPARγ for the treatment of nephrotic syndrome. Our recent data reveals that GQ-16, a more selective modulator of PPARγ, that binds to PPARγ distinctly from traditional agonist pioglitazone, reduces proteinuria and nephrotic syndrome-associated comorbidities in a rat model of minimal change disease with high efficacy, while resulting in reduced adipogenesis and lipid accumulation, compared to pioglitazone. Transcriptomic analyses revealed that pioglitazone and GQ-16 activate or restore common and distinct glomerular genes and pathways. These downstream effects in podocytes are likely directed by the PPARγ1 splice variant, distinct from the adipocyte-γ2 variant. Based on these findings, our central hypothesis is that PPARγ can be selectively modulated for better targeted therapeutic treatment for nephrotic syndrome with reduced side effects and that its podocyte-protective effects are regulated transcriptionally. To test our central hypothesis, we propose two Specific Aims: 1) Determine podocyte-specific direct transcriptional targets of PPARγ, and 2) Determine the beneficial role of selective modulation of PPARγ in treating nephrotic syndrome. Successful completion of these studies will advance the understanding of podocyte-specific PPARγ signaling and identify a potential therapeutic strategy to treat podocytopathies by a next generation PPARγ-modulator.

摘要 /项目摘要肾小球疾病表现为肾病综合征，具有高级蛋白尿和合并症，其特征是足细胞损伤和丧失，这是疾病进展的关键决定者。不幸的是，肾小球疾病经常对当前治疗产生难治性，从而导致慢性肾脏疾病和末期肾脏疾病的发展。这是一种未满足的医学需求，可以确定针对肾小球疾病的更有效且毒性更少的足细胞治疗方法。我们先前已经证明，在肾小球疾病的动物模型中，PPARγ激动剂和噻唑烷二酮（如吡格列酮），保护足细胞免受损伤，减少蛋白尿和肾小球损伤，并改善肾病综合征的临床结局。尽管取得了这些进步，但缺乏其足细胞特异性的机械理解和不必要的副作用阻碍了它们强大的临床应用。它们的宽度用作抗糖尿病药物也受到了审查，这导致了PPARγ的更有选择性调节剂的出现，这在最近的临床试验中显示了（NCT02638038）。由这些发展的动机并实现PPARγ调节的临床应用，在这里，我们试图摆脱传统的激动剂，朝着PPARγ的选择性调节以治疗肾病综合征。我们最近的数据表明，GQ-16是一种更具选择性的PPARγ调节剂，与PPARγ与传统的激动剂吡格列酮明显结合，可减少蛋白毒素和肾病综合征相关的合并症，在最小变化疾病的大鼠模型中，效率很高，导致脂肪源性降低和lipikecumation，与pecogation相比。转录组分析表明，吡格列酮和GQ-16激活或恢复常见和不同的肾小球基因和途径。这些下游效应在足细胞中可能是由PPARγ1剪接变体引导的，该变体与脂肪细胞-γ2变体不同。基于这些发现，我们的中心假设是，可以选择性地调节PPARγ，以便针对肾病综合征的更好靶向治疗，副作用降低，并且其足细胞保护作用受到转录的调节。为了检验我们的中心假设，我们提出了两个具体的目的：1）确定PPARγ的足细胞特异性直接转录靶标，以及2）确定PPARγ选择性调节在治疗肾病综合征中的有益作用。这些研究的成功完成将提高对足细胞特异性PPARγ信号传导的理解，并确定下一代PPARγ调节剂治疗足细胞病的潜在治疗策略。