A Novel Therapeutic Approach to Treat Focal Segmental Glomerulosclerosis (FSGS)

治疗局灶节段性肾小球硬化症 (FSGS) 的新方法

基本信息

批准号：
10513834
负责人：
Robert Spurney
金额：
$ 24.15万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10513834
关键词：
Address Adriamycin PFS Affect African American population Albuminuria Animal Model Apoptosis Apoptotic Atrial Natriuretic Factor Attenuated Binding Blood Circulation Brain Brain natriuretic peptide C-Type Natriuretic Peptide Calcium Calcium Signaling Cells Characteristics Cicatrix Cyclic GMP Diagnosis Disease Disease Progression End stage renal failure Endocrine system Epithelial Cells Etiology Focal Segmental Glomerulosclerosis Funding Opportunities Generations Goals Heart Heart Atrium Histologic Human Hypertension Immune system Incidence Injury Kidney Kidney Diseases Knock-out Knockout Mice Laboratories Ligands Mediating Medicare Modeling Mus NPR2 gene Natriuretic Peptides Nephrotic Syndrome Parietal Pathway interactions Patients Pattern Peptide Receptor Pharmacology Play Process Proteinuria Rare Diseases Renal glomerular disease Renin-Angiotensin System Resistance Role Signal Transduction Source Stimulus Therapeutic immunosuppression United States antagonist base cell type cost drug development experimental study hemodynamics in vivo inhibitor interest kidney cell mouse model novel novel therapeutic intervention novel therapeutics peptide analog podocyte preclinical study prevent protective effect receptor rho GTP-Binding Proteins translational potential

项目摘要

FSGS is characterized by segmental scarring of the glomerulus and nephrotic syndrome. Despite current therapies, ~50% of nephrotic patients progress to end stage kidney disease (ESKD) over a decade. As a result, there is much interest in developing new treatments. FSGS is defined by its characteristic histologic pattern, but the disease is caused by multiple, distinct etiologies, which share a final common pathway of podocyte injury and depletion. Because podocytes are terminally differentiated, postmitotic cells, podocytes that are lost cannot be effectively replaced, causing instability and collapse of the glomerular tuft, and disease progression. Treatment is focused on preventing podocyte injury and loss. Accumulating evidence suggests that cGMP signaling is podocyte protective in glomerular diseases. Natriuretic peptides (NPs) potently stimulate cGMP generation in podocytes by binding to NP receptors (NPRs). NPRA binds atrial NP (ANP) and brain NP (BNP), and NPRB binds the C-type NP (CNP). Podocyte specific knockout (KO) of the cGMP generating ANP/BNP receptor, NPRA, augments glomerular injury in proteinuric mouse models, indicating that NPs have podocyte protective actions. A negative regulator of NP actions is the clearance receptor NPRC, which binds and degrades ANP, BNP and CNP. Our preliminary experiments found: 1. Podocytes express NPRA, NPRB and NPRC. 2. NPs protect podocytes from apoptotic stimuli, 3. NPRC is highly expressed in podocytes and limits cGMP generation by locally available NPs, 4. Pharmacologic blockade of NPRC potentiates NPRA- and NPRB-induced cGMP generation in cultured podocytes and in vivo, and 5. Podocyte specific KO of NPRC reduces albuminuria in a mouse model of FSGS. The decrease in albuminuria in podocyte specific NPRC KO mice is unlikely to be mediated by systemic or hemodynamic mechanisms, and suggests a direct podocyte protective effect. Based on these findings, we hypothesized that blocking clearance of NPs by NPRC will elevate NP levels and promote podocyte protective cGMP signaling. Aim 1 will study the effect of podocyte specific KO of NPRC in 1. A mouse model of FSGS created in our laboratory (model 1), and 2. The Adriamycin model of FSGS (model 2). Aim 2 exams pharmacologic blockade of NPRC in model 1 using a novel NPRC antagonist. Current NPRC ligands are peptide analogs of ANP, which are rapidly degraded in the circulation. This novel ligand is resistant to degradation and robustly enhances cGMP generation in vivo compared to currently available NPRC ligands. The proposed studies address the goals of the funding opportunity by "performing proof of concept studies in an animal model of a rare disease". These experiments will establish "proof of concept" and provide the rationale for developing effective, degradation resistant inhibitors of NP clearance. Development of these drugs will provide the basis for preclinical studies using pharmacologic inhibitors of NP clearance to elevate NP levels and cGMP signaling in podocytes and, in turn, reduce glomerular injury in FSGS.

FSGS 的特点是肾小球节段性疤痕和肾病综合征。尽管目前治疗后，约 50% 的肾病患者在十年内进展为终末期肾病 (ESKD)。因此，人们对开发新疗法很感兴趣。 FSGS 由其特征性组织学模式定义，但是该疾病是由多种不同的病因引起的，它们具有足细胞损伤的最终共同途径和耗尽。由于足细胞是终末分化的，有丝分裂后细胞，丢失的足细胞不能被有效替换，导致肾小球簇不稳定和塌陷，以及疾病进展。治疗的重点是防止足细胞损伤和丢失。越来越多的证据表明 cGMP 信号传导在肾小球疾病中具有足细胞保护作用。利钠肽 (NP) 有效刺激 cGMP 通过与 NP 受体 (NPR) 结合在足细胞中产生。 NPRA 结合心房 NP (ANP) 和脑 NP (BNP)， NPRB结合C型NP(CNP)。产生 ANP/BNP 的 cGMP 足细胞特异性敲除 (KO) 受体 NPRA 会增强蛋白尿小鼠模型中的肾小球损伤，表明 NP 具有足细胞保护行动。 NP 作用的负调节因子是清除受体 NPRC，它结合并降解 ANP、BNP 和 CNP。我们的初步实验发现： 1.足细胞表达NPRA、NPRB和NPRC。 2. NPs 保护足细胞免受凋亡刺激，3. NPRC 在足细胞中高表达并限制 cGMP 4. NPRC 的药理学阻断可增强 NPRA 和 NPRB 诱导的培养的足细胞和体内的 cGMP 生成，以及 5. NPRC 足细胞特异性 KO 减少白蛋白尿在 FSGS 小鼠模型中。足细胞特异性 NPRC KO 小鼠白蛋白尿的减少不太可能是由于由全身或血流动力学机制介导，表明具有直接的足细胞保护作用。基于根据这些发现，我们假设 NPRC 阻断 NP 的清除将提高 NP 水平并促进足细胞保护性 cGMP 信号传导。目标 1 将研究 NPRC 足细胞特异性 KO 对 1. 小鼠的影响我们实验室创建的 FSGS 模型（模型 1）和 2. FSGS 的阿霉素模型（模型 2）。目标2 使用新型 NPRC 拮抗剂检查模型 1 中 NPRC 的药理学阻断作用。目前的 NPRC 配体是 ANP 的肽类似物，在循环中迅速降解。这种新型配体能够抵抗与目前可用的 NPRC 配体相比，它可以降解并显着增强体内 cGMP 的生成。拟议的研究通过“在一个特定的环境中进行概念验证研究”来解决资助机会的目标一种罕见疾病的动物模型”。这些实验将建立“概念验证”并提供开发有效的、抗降解的 NP 清除抑制剂的基本原理。发展这些药物将为使用 NP 清除的药物抑制剂进行临床前研究提供基础提高足细胞中的 NP 水平和 cGMP 信号传导，进而减少 FSGS 中的肾小球损伤。