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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病因不明的结缔组织疾病，影响皮肤、肺和其他内脏器官，机关该疾病的特征是免疫功能障碍、血管病理、慢性炎症，成纤维细胞过度增殖和胶原蛋白积聚。虽然有有限的治疗选择，包括免疫抑制药物，这些疗法只能缓解症状，但无法逆转既定的纤维化和治疗硬皮病。因此，有机会开发新的抗纤维化疗法，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配制的类似物（创造的德马拉唑）可能阻止硬皮病进展。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，以发现调节组织中所涉及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，给予埃索美拉唑抑制肺部炎症和纤维化达50%。研究还表明埃索美拉唑是抗增殖的，对成纤维细胞增殖和分化具有深远的影响，肌成纤维细胞受此鼓舞，我们最近将埃索美拉唑重新配制为德马拉唑，治疗皮肤受累有限的硬皮病，而全身性埃索美拉唑正在是为治疗严重的疾病而开发的我们的数据使用人类3D皮肤模型，真皮成纤维细胞分离从硬皮病患者，和硬皮病的小鼠模型表明，这两种形式的药物是有效抑制纤维化和恢复正常皮肤外观。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。我们的分子生物学研究表明，埃索美拉唑/德马拉唑通过细胞核调节纤维化转录因子核因子红细胞2相关因子2（Nrf 2）易位激活血红素加氧酶1（HO 1），并抑制关键的细胞外基质（ECM）蛋白。分子研究还表明，埃索美拉唑对HO 1的激活涉及促分裂原活化蛋白激酶（MAPK）的磷酸化通路因此，我们计划测试我们的中心假设：埃索美拉唑/德马拉唑能够减缓或以MAPK/Nrf 2/HO 1依赖的方式阻止硬皮病中已建立的纤维化。为了验证这一点，我们建议以下具体目的：i）了解埃索美拉唑激活HO 1以控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Nrf 2之间激活HO 1及其效应物，以及调查是否在硬皮病成纤维细胞增殖的调节中需要埃索美拉唑激活Nrf 2/HO 1，胶原沉积ii）评价埃索美拉唑/德马拉唑在调节皮肤和肺中的功效使用硬皮病的野生型、Nrf 2和MAPK敲除小鼠模型进行体内纤维化。