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伴有高级别蛋白尿并伴有并发症的肾病综合征，其特征是足细胞损伤和丢失，这是疾病进展的关键决定因素。不幸的是，肾小球疾病通常对当前的治疗无效，导致进展为慢性肾病。因此，寻找更有效、毒性更小的足细胞靶向治疗肾小球疾病的医学需求尚未得到满足。激动剂和噻唑烷二酮类药物（如吡格列酮）可保护足细胞免受损伤，减少肾小球疾病动物模型中的蛋白尿和肾小球损伤，并改善肾病综合征的临床结果尽管取得了这些进展，但仍缺乏对足细胞特异性机制的了解和不良副作用。阻碍了它们作为抗糖尿病药物的广泛应用也受到了审查，但这导致了更具选择性的调节剂的出现。 PPARγ 在最近的临床试验中表现出了希望（NCT02638038）。受这些发展的推动，为了实现 PPARγ 调节的临床应用，我们寻求摆脱传统的激动剂，转向选择性调节 PPARγ 来治疗肾病综合征。最近的数据表明，GQ-16 是一种更具选择性的 PPARγ 调节剂，与 PPARγ 的结合与传统激动剂吡格列酮不同，可减少与吡格列酮相比，在微小病变性疾病大鼠模型中，蛋白尿和肾病综合征相关的合并症具有高效性，同时导致脂肪生成和脂质积累减少，转录组分析表明，吡格列酮和 GQ-16 激活或恢复常见和独特的肾小球基因，足细胞中的这些下游效应可能是由 PPARγ1 剪接变体引导的，与脂肪细胞-γ2 变体不同。基于这些发现，我们的中心假设是。是可以选择性地调节 PPARγ 以更好地靶向治疗肾病综合征，同时减少副作用，并且其足细胞保护作用是通过转录调节的。为了检验我们的中心假设，我们提出了两个具体目标：1）确定足细胞特异性的直接转录。 PPARγ 的靶点，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增进对 PPARγ 的认识。足细胞特异性 PPARγ 信号传导，并确定通过下一代 PPARγ 调节剂治疗足细胞病的潜在治疗策略。