Role of PAPP-A in Pulmonary Fibrosis

PAPP-A 在肺纤维化中的作用

• 批准号: 10261323
• 负责人: Cheryl A. Conover
• 金额: $ 19.88万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-15 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10261323
• 关键词: Adult; Age; Aging; Apoptosis; Biological Availability; Bleomycin; Cell Survival; Cell membrane; Cleaved cell; Clinical Trials; Data; Deposition; Development; Disease; Elderly; Enzymes; Etiology; Extracellular Matrix; Feedback; Fibroblasts; Fibrosis; Gene Deletion; Gene Expression; Growth; Human; In Vitro; Inflammatory; Injury; Insulin-Like Growth Factor Binding Protein 4; Insulin-Like Growth Factor I; Insulin-Like Growth Factor Receptor; Insulin-Like-Growth Factor I Receptor; Knowledge; Lead; Lung; Lung diseases; Malignant Neoplasms; Metabolism; Metalloproteases; Modeling; Mus; Nature; Pathogenicity; Patients; Pregnancy-Associated Plasma Protein-A; Process; Production; Proteolysis; Publishing; Pulmonary Fibrosis; Receptor Activation; Receptor Signaling; Regulation; Role; Signal Transduction; Site; Somatomedins; System; Testing; Therapeutic; Transforming Growth Factors; Work; Zinc; age related; base; cell type; cytokine; effective therapy; experimental study; extracellular vesicles; idiopathic pulmonary fibrosis; in vivo; innovation; lung injury; migration; mouse model; neutralizing monoclonal antibodies; novel; novel therapeutics; receptor; response to injury; restraint; side effect; therapeutic target; wound healing; wound response

PROJECT SUMMARY Idiopathic pulmonary fibrosis (IPF) is an age-associated fatal lung disease of unknown etiology, and patients with IPF have few therapeutic options. Therefore, it is important to explore new pathogenic mechanisms underlying development of the fibrosis, and to identify potential therapeutic targets for this deadly disease. Transforming growth factor (TGF)-β is a major fibrogenic factor. However, TGF-β appears to work synergistically with other factors to direct and promote excessive fibrosis. One of these is insulin-like growth factor (IGF)-I. Nevertheless, there are large gaps in our knowledge about the role of IGF receptor activation in the initiation and/or progression of pulmonary fibrosis. Furthermore, there are concerns about its usefulness as a direct therapeutic target. We suggest an alternative approach. We discovered a novel zinc metalloproteinase, PAPP-A, that enhances local IGF action through specific cleavage of inhibitory IGF binding protein-4 in many cell types, including fibroblasts. We have shown that pro-inflammatory cytokines associated with the wounding response are potent stimulators of PAPP-A expression. Our preliminary data indicate that TGF-β can also stimulate PAPP-A expression in lung fibroblasts. Inhibition of PAPP-A expression or its proteolytic activity represents an innovative approach to decreasing IGF availability with moderate restraint of IGF receptor signaling. We have shown that inhibition of PAPP-A through gene deletion in mice has many beneficial effects on aging-related diseases. We can also inhibit the ability of PAPP-A to cleave IGFBP-4 in vitro and in vivo with a novel neutralizing monoclonal antibody generated against a unique exosite in PAPP-A. Specific Aim 1 will focus on the regulation and function of PAPP-A in human lung fibroblasts in vitro, but will include assessment of other components of the IGF system that could be novel contributors to fibrosis. Experiments in this aim will also determine the effect of PAPP-A-regulated IGF-I bioavailability on proliferation, migration, extracellular matrix production, and apoptosis. Specific Aim 2 will test the hypothesis that inhibition of PAPP-A gene expression or its proteolytic activity reduces the development of fibrosis in a mouse lung injury model. Preliminary data indicate increased PAPP-A expression in lungs of mice following a bleomycin-induced injury, and intense PAPP-A immunostaining at fibroblastic foci in lungs from patients with IPF. Thus, we propose exploratory in vitro and in vivo studies to test novel hypotheses with anticipated results that could ultimately lead to a novel therapy for patients with IPF.

项目摘要 特发性肺纤维化（IPF）是一种病因不明的与年龄相关的致命性肺部疾病， IPF患者的治疗选择很少。因此，探索新的致病机制具有重要意义 纤维化的潜在发展，并确定这种致命疾病的潜在治疗靶点。 转化生长因子（TGF）-β是一种主要的纤维化因子。然而，TGF-β似乎起作用 与其它因子协同作用以引导和促进过度纤维化。其中之一就是胰岛素样生长 因子（IGF）-I。尽管如此，我们对IGF受体激活在胰岛素抵抗中的作用的认识还有很大的差距。 肺纤维化的开始和/或进展。此外，有人担心它的用处， 一个直接的治疗目标我们建议另一种方法。我们发现了一种新的锌金属蛋白酶， PAPP-A，通过特异性切割抑制性IGF结合蛋白-4增强局部IGF作用，在许多 细胞类型，包括成纤维细胞。我们已经证明，与创伤相关的促炎细胞因子 反应是PAPP-A表达的有效刺激物。我们的初步数据表明，TGF-β也可以 刺激肺成纤维细胞中PAPP-A表达。PAPP-A表达或其蛋白水解活性的抑制 代表了一种通过适度限制IGF受体来降低IGF可用性的创新方法 发信号。我们已经证明，通过基因缺失抑制小鼠的PAPP-A具有许多有益的效果 与衰老有关的疾病。我们还可以在体外和体内抑制PAPP-A切割IGFBP-4的能力， 一种针对PAPP-A中独特的外切位点产生的新型中和单克隆抗体。 具体目标1将集中于体外人肺成纤维细胞中PAPP-A的调节和功能，但将 包括评估IGF系统中可能是纤维化新贡献者的其他成分。 为此目的的实验还将确定PAPP-A调节的IGF-I生物利用度对增殖的影响， 迁移、细胞外基质产生和细胞凋亡。具体目标2将检验抑制 PAPP-A基因表达或其蛋白水解活性降低小鼠肺损伤中纤维化的发展 模型初步数据表明，在博来霉素诱导的小鼠肺内PAPP-A表达增加， 损伤和IPF患者肺中成纤维细胞灶处的强PAPP-A免疫染色。 因此，我们提出了探索性的体外和体内研究，以测试新的假设与预期的结果， 最终可能为IPF患者带来一种新的治疗方法。