Repurposing esomeprazole for the treatment of scleroderma

重新利用埃索美拉唑治疗硬皮病

基本信息

批准号：
10535112
负责人：
Yohannes T Ghebre
金额：
$ 5.65万
依托单位：
BAYLOR COLLEGE OF MEDICINE
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：
2022-08-17 至 2022-12-03
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10535112
关键词：
3-Dimensional Affect Animal Disease Models Animal Model Animals Anti-Inflammatory Agents Appearance Binding Binding Sites Biological Blood Vessels Cell Nucleus Cells Cessation of life Chronic Chronic Disease Coin Collagen Connective Tissue Diseases Cream Cutaneous Involvement Data Deposition Dermal Development Diffuse Disease Distant Environmental Risk Factor Esomeprazole Etiology Extracellular Matrix Proteins FDA approved Family Fibroblasts Fibrosis Genetic Human Image Immune Immune System Diseases Immunosuppressive Agents In Vitro Inflammation Inflammatory Knockout Mice Lung Mediating Mitogen-Activated Protein Kinases Modeling Molecular Multiple Organ Failure Mus Myofibroblast Nuclear Translocation Oral Organ Pathology Pathway interactions Patients Pharmaceutical Preparations Pharmacotherapy Phosphorylation Process Promoter Regions Pulmonary Fibrosis Pulmonary Inflammation Regulation Research Scleroderma Secondary to Skin Systemic Scleroderma Testing Tissues Topical application Transforming Growth Factor beta Universities Visceral analog antifibrotic treatment base efficacy evaluation fibrogenesis heme oxygenase-1 high throughput screening in vivo insight knockout animal member mouse model novel nuclear factor-erythroid 2 reduce symptoms skin fibrosis small molecule standard of care targeted treatment transcription factor transdifferentiation

项目摘要

PROJECT SUMMARY Scleroderma is a connective tissue disorder of unknown etiology affecting the skin, lungs and other visceral organs. The disease is characterized by immune dysfunction, vascular pathology, chronic inflammation, fibroblast overproliferation and collagen buildup. Although there are limited treatment options including immunosuppressive drugs, these therapies only alleviate symptoms but are unable to reverse established fibrosis and cure scleroderma. Thus, there is an opportunity to develop novel antifibrotic therapies that target chief drivers of the disease: fibroblast overproliferation and collagen accumulation. According to our new study, esomeprazole and its topically-formulated analog (coined Dermaprazole) might halt progression of scleroderma. This understanding is based on our extended studies of high throughput screening (HTS) 130,000 small molecules to discover compounds that regulate processes involved in tissue inflammation and fibrosis. Our molecular, cell biological and in vivo data demonstrate that systemic administration of esomeprazole inhibits lung inflammation and fibrosis by 50%. The study also showed that esomeprazole is anti-proliferative with profound effect on fibroblast proliferation, and differentiation into myofibroblasts. Encouraged by these, we recently reformulated esomeprazole into Dermaprazole for the treatment of scleroderma with limited cutaneous involvement, while the systemic esomeprazole is being developed for severe forms of the disease. Our data using human 3D skin model, dermal fibroblasts isolated from scleroderma patients, and mouse models of scleroderma demonstrated that both forms of the drug are effective in inhibiting fibrosis and restoring normal skin appearance. In addition, systemic esomeprazole was found to suppress lung fibrosis secondary to skin fibrosis in a model of systemic sclerosis. Our molecular studies indicate that esomeprazole/Dermaprazole modulate fibrosis through nuclear translocation of the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) to activate heme oxygenase 1 (HO1), and suppress key extracellular matrix (ECM) proteins. Molecular studies also show that activation of HO1 by esomeprazole involves phosphorylation of the Mitogen-Activated Protein Kinase (MAPK) pathway. Accordingly, we plan to test our central hypothesis: esomeprazole/Dermaprazole is able to slow or halt established fibrosis in scleroderma in MAPK/Nrf2/HO1 dependent manner. To test this, we propose the following Specific Aims: i) Understand the mechanism(s) by which esomeprazole activates HO1 to control inflammatory and fibrotic processes in scleroderma. In this Aim, we will evaluate the mechanistic interaction between esomeprazole, MAPK and Nrf2 to activate HO1 and its effectors, as well as investigate whether activation of Nrf2/HO1 by esomeprazole is required in the regulation of scleroderma fibroblast proliferation and collagen deposition. ii) Evaluate the efficacy of esomeprazole/Dermaprazole in modulating dermal and lung fibrosis in vivo using wildtype, Nrf2, and MAPK knockout mouse models of scleroderma.

项目概要硬皮病是一种病因不明的结缔组织疾病，影响皮肤、肺部和其他内脏器官器官。该疾病的特点是免疫功能障碍、血管病理、慢性炎症、成纤维细胞过度增殖和胶原蛋白堆积。尽管治疗选择有限，包括免疫抑制药物，这些疗法只能缓解症状，但无法逆转已建立的纤维化并治愈硬皮病。因此，有机会开发针对目标的新型抗纤维化疗法该疾病的主要驱动因素：成纤维细胞过度增殖和胶原蛋白积累。根据我们的新研究，埃索美拉唑及其外用制剂类似物（创造的德马普拉唑）可能阻止硬皮病的进展。这种理解基于我们对高通量的深入研究筛选 (HTS) 130,000 个小分子，发现调节组织过程的化合物炎症和纤维化。我们的分子、细胞生物学和体内数据表明，系统性埃索美拉唑可抑制肺部炎症和纤维化 50%。研究还表明埃索美拉唑具有抗增殖作用，对成纤维细胞增殖和分化有深远影响肌成纤维细胞。受这些因素的鼓励，我们最近将埃索美拉唑重新配制为德马拉唑，用于治疗仅限皮肤受累的硬皮病，同时全身使用埃索美拉唑专为治疗严重疾病而开发。我们的数据使用人体 3D 皮肤模型，分离出真皮成纤维细胞来自硬皮病患者的硬皮病小鼠模型表明，这两种形式的药物均有效有效抑制纤维化，恢复正常皮肤外观。此外，全身埃索美拉唑发现在系统性硬化症模型中抑制继发于皮肤纤维化的肺纤维化。我们的分子研究表明埃索美拉唑/德马拉唑通过核调节纤维化转录因子核因子红细胞 2 相关因子 2 (Nrf2) 易位以激活血红素加氧酶 1 (HO1)，并抑制关键的细胞外基质 (ECM) 蛋白。分子研究还表明埃索美拉唑激活 HO1 涉及丝裂原激活蛋白激酶 (MAPK) 的磷酸化途径。因此，我们计划检验我们的中心假设：埃索美拉唑/德马拉唑能够减缓或以 MAPK/Nrf2/HO1 依赖性方式停止硬皮病中已形成的纤维化。为了测试这一点，我们建议以下具体目标： i) 了解埃索美拉唑激活 HO1 来控制的机制硬皮病的炎症和纤维化过程。在这个目标中，我们将评估机械相互作用埃索美拉唑、MAPK 和 Nrf2 之间激活 HO1 及其效应子，并研究是否埃索美拉唑激活 Nrf2/HO1 在调节硬皮病成纤维细胞增殖和胶原沉积。 ii) 评估埃索美拉唑/德马拉唑调节皮肤和肺部的功效使用硬皮病野生型、Nrf2 和 MAPK 敲除小鼠模型进行体内纤维化。