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：
10250666
负责人：
Yohannes T Ghebre
金额：
$ 35.2万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-10 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10250666
关键词：
3-Dimensional Acidity Affect Animal Disease Models Animal Model Animals Anti-Inflammatory Agents Antioxidants Appearance Binding Sites Biological Bleomycin Blood Vessels Breeding Cell Nucleus Cells Cessation of life Chronic Chronic Disease Coin Collagen Connective Tissue Diseases Cutaneous Involvement Data Deposition Dermal Development Diffuse Scleroderma Disease Distant Environmental Risk Factor Esomeprazole Etiology Extracellular Matrix FDA approved Family Fibroblasts Fibronectins Fibrosis Genetic Grant Human Immune Immune System Diseases In Vitro Incidence Inflammation Inflammatory Knock-out Knockout Mice Lung Lung Inflammation Mediating Mitogen-Activated Protein Kinases Modeling Molecular Multiple Organ Failure Mus Nuclear Translocation Organ Oxidative Stress Parents Pathology Pathway interactions Patients Pharmaceutical Preparations Pharmacotherapy Preparation Process Promoter Regions Proton Pump Inhibitors Publishing Pulmonary Fibrosis Radiation Reducing Agents Regulation Research Scleroderma Skin Stomach Systemic Scleroderma Testing Tissues Topical application United States Universities Up-Regulation Visceral analog base curative treatments fibrogenesis heme oxygenase-1 high throughput screening in vivo innovation insight knockout animal member mouse model novel novel therapeutics nuclear factor-erythroid 2 reduce symptoms skin disorder small molecule standard of care targeted treatment therapeutic evaluation transcription factor

3-Dimensional Acidity Affect Animal Disease Models Animal Model Animals Anti-Inflammatory Agents Antioxidants Appearance Binding Sites Biological Bleomycin Blood Vessels Breeding Cell Nucleus Cells Cessation of life Chronic Chronic Disease Coin Collagen Connective Tissue Diseases Cutaneous Involvement Data Deposition Dermal Development Diffuse Scleroderma Disease Distant Environmental Risk Factor Esomeprazole Etiology Extracellular Matrix FDA approved Family Fibroblasts Fibronectins Fibrosis Genetic Grant Human Immune Immune System Diseases In Vitro Incidence Inflammation Inflammatory Knock-out Knockout Mice Lung Lung Inflammation Mediating Mitogen-Activated Protein Kinases Modeling Molecular Multiple Organ Failure Mus Nuclear Translocation Organ Oxidative Stress Parents Pathology Pathway interactions Patients Pharmaceutical Preparations Pharmacotherapy Preparation Process Promoter Regions Proton Pump Inhibitors Publishing Pulmonary Fibrosis Radiation Reducing Agents Regulation Research Scleroderma Skin Stomach Systemic Scleroderma Testing Tissues Topical application United States Universities Up-Regulation Visceral analog base curative treatments fibrogenesis heme oxygenase-1 high throughput screening in vivo innovation insight knockout animal member mouse model novel novel therapeutics nuclear factor-erythroid 2 reduce symptoms skin disorder small molecule standard of care targeted treatment therapeutic evaluation transcription factor

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项目摘要

PROJECT SUMMARY Systemic sclerosis (scleroderma) is a deadly 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. Current estimates of disease incidence are 20 cases per million and include about 100,000 cases in the United States. 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, the parent compound esomeprazole and its topically-formulated analog (coined Dermaprazole) might be novel therapy to halt progression of scleroderma. This understanding is based on our extended studies of high throughput screening (HTS) 130,000 small molecules to discover and validate compounds that regulate processes involved in tissue inflammation and fibrosis. Our published molecular, cell biological and in vivo data demonstrate that systemic administration of esomeprazole inhibits bleomycin- induced lung inflammation and fibrosis by 50%. The study also showed that esomeprazole is anti-proliferative with profound effect on fibroblast proliferation. Encouraged by these, we recently reformulated esomeprazole into Dermaprazole for the treatment of scleroderma with limited cutaneous involvement, while the systemically administered esomeprazole is being developed for severe forms of scleroderma. Our data using human 3D skin model, dermal fibroblasts isolated from scleroderma patients, and mouse model of scleroderma revealed that both forms of the drug are effective in blocking collagen buildup and restoring normal skin appearance. Our molecular studies indicate that esomeprazole/Dermaprazole simultaneously modulates oxidative stress, inflammation and fibrosis through upregulation of the master antioxidant and cytoprotective pathway: nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase 1 (HO1), and suppression of key extracellular matrix (ECM) components such as collagen and fibronectin. Accordingly, we plan to test our central hypothesis “the antioxidant and antifibrotic actions of esomeprazole are able to slow or halt established fibrosis in scleroderma”. 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 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 and Nrf2 knockout mouse models of scleroderma. This is an innovative project proposing to repurpose a promising drug to effectively slow or halt scleroderma.

项目摘要全身性硬化症（硬皮病）是一种致命联系的组织障碍，患有病因，影响皮肤，肺部和其他内脏器官。该疾病的特征是免疫功能障碍，血管病理学，慢性炎症，成纤维细胞过度增殖和胶原蛋白积累。当前疾病事件的估计值在美国有20例，其中约为100,000例。虽然有限治疗选择在内，包括免疫抑制药物，这些疗法仅减轻症状，但无法逆转确定的纤维化并治愈硬皮病。那是有机会发展新颖的抗纤维化针对该疾病的主要驱动因素的疗法：成纤维细胞过度增殖和胶原蛋白积累。根据我们的新研究，母体复合埃索美拉唑及其原则成型的类似物（创造皮肤酸）可能是阻止硬皮病进展的新型疗法。这种理解是基于我们的高通量筛选（HTS）的扩展研究130,000个小分子以发现和验证调节参与组织注射和纤维化的过程的化合物。我们发表的分子细胞生物学和体内数据表明，全身性埃塞美拉唑抑制博来霉素 - 诱导肺注射和纤维化50％。该研究还表明，埃索美拉唑是反增殖的对成纤维细胞增殖有深远的影响。在这些鼓励下，我们最近改革了埃塞美拉唑进入皮肤帕唑以有限的皮肤参与治疗硬皮病，而系统地则正在为严重的硬皮病形式开发埃索美拉唑。我们使用人类3D的数据皮肤模型，从硬皮病患者中分离出的皮肤成纤维细胞和硬皮病的小鼠模型显示两种形式的药物都可以有效地阻断胶原蛋白的堆积并恢复正常的皮肤外观。我们的分子研究表明，埃索美丙唑/皮拉唑只是调节氧化应激，通过上调主抗氧化剂和细胞保护途径，炎症和纤维化：核因子红细胞2相关因子2（NRF2）/血红素氧酶1（HO1），并抑制钥匙外基质基质（ECM）胶原蛋白和纤连蛋白等成分。根据，我们计划检验我们的中心假设“ 埃索美拉唑的抗氧化剂和抗纤维化作用能够减慢或停止建立的纤维化 scleroderma”。为了测试这一点，我们提出了以下具体目的：i）了解该机制 Esomeprazole激活HO1以控制硬皮病中的炎症和纤维化过程。在这个目标中，我们将评估埃索美拉唑和NRF2之间的机械相互作用，以激活HO1及其效果如调查在硬皮病调节中是否需要通过埃索美拉唑激活NRF2/HO1 成纤维细胞增殖和胶原蛋白沉积。 ii）评估在使用硬皮病的野生型和NRF2敲除小鼠模型在体内调节皮肤和肺纤维化。这是一个创新的项目，建议将承诺药物重新利用以有效缓慢或停止硬皮病。