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：
10794118
负责人：
Yohannes T Ghebre
金额：
$ 53.25万
依托单位：
UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-02-23 至 2028-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10794118
关键词：
Repurposing esomeprazole treatment scleroderma

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.

项目摘要硬皮病是一种未知病因的结缔组织障碍，影响了皮肤，肺和其他内脏器官。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堆积。尽管治疗选择有限，包括免疫抑制药物，这些疗法仅减轻症状，但无法逆转纤维化和治愈硬皮病。因此，有机会开发针对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，埃索美拉唑及其局部形成的类似物（含称的dermaprazole）可能硬皮病的停止进展。这种理解是基于我们对高通量的扩展研究筛选（HTS）130,000个小分子，发现调节参与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了全身性埃森美吡唑施用抑制肺部炎症和纤维化50％。研究还表明埃索美拉唑是抗增殖性的，对成纤维细胞增殖有深远影响，并分化为肌纤维细胞。在这些鼓励下，我们最近将埃索美拉唑重新出发到dermaprazole 皮硬皮病的治疗有限的皮肤受累，而全身性埃索美拉唑则是为严重的疾病形式开发。我们使用人类3D皮肤模型的数据，皮肤成纤维细胞隔离从硬皮病患者和硬皮病的小鼠模型表明，两种形式的药物都是有效抑制纤维化并恢复正常皮肤外观。此外，全身性埃索美拉唑是发现在系统性硬化症模型中抑制皮肤纤维化继发的肺纤维化。我们的分子研究表明，埃索美拉唑/肾上腺酸通过核调节纤维化转录因子核因子核因子2相关因子2（NRF2）的易位以激活血红素氧合酶1（HO1），并抑制钥匙细胞外基质（ECM）蛋白。分子研究还表明埃索美丙唑激活HO1涉及有丝分裂原激活蛋白激酶（MAPK）的磷酸化路径。因此，我们计划检验我们的中心假设：埃索美拉唑/dermaprazole能够减速或在MAPK/NRF2/HO1依赖性方式中，停止在硬皮病中建立了纤维化。为了测试这一点，我们提出了以下特定目的：i）了解埃索美拉唑激活HO1以控制的机制硬皮病中的炎症和纤维化过程。在此目标中，我们将评估机械互动在Esomeprazole，MAPK和NRF2之间激活HO1及其效应子，并调查是否是否在硬皮o虫成纤维细胞增殖和胶原蛋白沉积。 ii）评估埃索美拉唑/皮拉唑在调节皮肤和肺部的功效使用野生型，NRF2和MAPK敲除小鼠模型在体内纤维化。