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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：
10670414
负责人：
Robert Spurney
金额：
$ 20.13万
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 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10670414
关键词：
Address Adriamycin PFS Affect African American population Albuminuria Animal Model Apoptosis Apoptotic Atrial Natriuretic Factor Attenuated Binding Brain natriuretic peptide C-Type Natriuretic Peptide Calcium Calcium Signaling Cells Characteristics Cicatrix Circulation Cyclic GMP Cytoprotection Diagnosis Disease Disease Progression End stage renal failure Endocrine system Epithelial Cells Etiology Focal and Segmental Glomerulosclerosis Funding Opportunities Generations Goals Heart Histologic Human 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 Play Process Proteinuria Rare Diseases Renal glomerular disease Renin-Angiotensin System Resistance Role Signal Transduction Stimulus Therapeutic immunosuppression United States antagonist cell type cost drug development experimental study hemodynamics hypertension control in vivo inhibitor interest kidney cell mouse model novel novel therapeutic intervention novel therapeutics peptide analog pharmacologic podocyte postmitotic preclinical study prevent protective effect receptor rho GTP-Binding Proteins source localization 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以肾小球节段性瘢痕形成和肾病综合征为特征。尽管目前尽管有多种治疗，约50%的肾病患者在十年内进展为终末期肾病（ESKD）。因此，在本发明中，人们对开发新的治疗方法很感兴趣。FSGS由其特征性组织学模式定义，但这种疾病是由多种不同的病因引起的，这些病因共有一个最终共同的足细胞损伤途径和消耗。因为足细胞是终末分化的，有丝分裂后的细胞，丢失的足细胞不能这导致肾小球簇的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损失。越来越多的证据表明cGMP 信号传导在肾小球疾病中是足细胞保护性的。利钠肽（NPs）有效刺激cGMP 通过结合NP受体（NPR）在足细胞中产生。NPRA结合心房NP（ANP）和脑NP（BNP），而NPRB结合C型NP（CNP）。产生ANP/BNP的cGMP的足细胞特异性敲除（KO）在蛋白尿小鼠模型中，NPRA受体增强肾小球损伤，表明NPs具有足细胞保护行动。NP作用的负调节剂是清除受体NPRC，其结合并降解 ANP、BNP和CNP。我们的初步实验发现：1.足细胞表达NPRA、NPRB和NPRC。2. 纳米颗粒保护足细胞免受凋亡刺激，3。NPRC在足细胞中高度表达并限制cGMP 通过本地可用的NP生成，4. NPRC的药理学阻断增强NPRA和NPRB诱导的在培养的足细胞和体内的cGMP生成，和5. NPRC的足细胞特异性KO减少蛋白尿在FSGS的小鼠模型中。足细胞特异性NPRC KO小鼠中白蛋白尿的减少不太可能是由于通过全身或血液动力学机制介导，并表明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，足细胞保护性cGMP信号传导。目的1研究NPRC对足细胞特异性KO的影响。鼠标模型的FSGS创建在我们的实验室（模型1），和2。阿霉素FSGS模型（模型2）。目的2 在模型1中使用新型NPRC拮抗剂检查NPRC的药理学阻断。目前的NPRC配体是 ANP的肽类似物，其在循环中快速降解。这种新的配体对与目前可用的NPRC配体相比，NPRC配体降解并在体内稳健地增强cGMP产生。拟议的研究通过“在一个国家进行概念验证研究”来解决资助机会的目标。罕见疾病的动物模型”。这些实验将建立“概念证明”，并提供开发有效的、耐降解的NP清除抑制剂的基本原理。发展这些药物将为使用NP清除的药理学抑制剂的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。