Synthetic Oleananes: Innovative Treatment of Fibrosis

合成齐墩果烷：纤维化的创新治疗方法

• 批准号: 8774095
• 负责人: Jun Wei
• 金额: $ 7.73万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8774095
• 关键词: 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid; Adherent Culture; Affect; Antioxidants; Attenuated; Autoimmune Responses; Autoimmunity; Bleomycin; Cells; Chronic; Cicatrix; Clinical; Clinical Treatment; Clinical Trials; Collaborations; Development; Disease; Drug Kinetics; Erythroid; Evolution; Excess Mortality; Fibroblasts; Fibrosis; Future; Generations; Genetic; Goals; Health; Human; Immune; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Lead; Light; Lung; Mediating; Medical; Modeling; Morbidity - disease rate; Motion; Mus; Myofibroblast; Nuclear; Oleanolic Acid; Organ; Organ Culture Techniques; Organ failure; Organoids; Outcome; Oxidative Stress; Pathogenesis; Patients; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Phenotype; Prevention; Process; Property; Reactive Oxygen Species; Role; Safety; Scleroderma; Signal Transduction; Skin; Systemic Scleroderma; Testing; Therapeutic; Toxicology; Transforming Growth Factors; Validation; Work; base; clinical application; disability; effective therapy; healthy volunteer; in vitro activity; in vivo; injured; innovation; medical schools; mortality; mouse model; novel; novel therapeutic intervention; oleanane; prevent; research study; response; synthetic drug; therapeutic target; transcription factor

DESCRIPTION (provided by applicant): Greater than 50% of patients with the aggressive form of the systemic sclerosis (SSc) die or develop organ failure within 5 years, and standardized mortality rates have remained unchanged over past four decades. Skin and lung fibrosis are major causes of morbidity and mortality, and have no approved treatment. Fibrosis results from myofibroblast activation in injured microenvironments, initiated and sustained by inflammatory cells, transforming growth factor-ss (TGF-ss) and reactive oxygen species (ROS). Dissecting the intracellular signaling networks controlling the process can lead to the discovery of therapeutic targets. I showed that CDDO, a synthetic derivative of the naturally occurring oleanolic acid, inhibit myofibroblast differentiation and attenuate fibrosis in two distinct mouse models of scleroderma. Therefore CDDO and related synthetic oleananes (SOs) with drug-like properties represent a potential therapeutic approach to fibrosis. Furthermore, I recently identified a potentially critical role for Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) in regulating myofibroblast activation and development of fibrosis, and mediating anti-fibrotic effects of CDDO. My hypothesis is that second-generation SOs with excellent safety profile will demonstrate Nrf2-mediated anti-fibrotic effects in fibroblasts, and will mitigate the key pathogenetic features of SSc (immune dysregulation, oxidative stress and fibrosis) and result in reduced fibroblast activation, reversal of the myofibroblast phenotype and mitigated organ fibrosis in mouse models. Working in collaboration with Drs. Liby and Sporn (Pharmacology, Dartmouth Medical School), I will i) examine anti-fibrotic effects of two second-generation SOs with high potency to induce Nrf2 activity in vitro using explanted fibroblasts, human skin equivalents and skin organoids, and explore the mechanism of action; ii) evaluate their ability to prevent, as well as to reverse, fibrosis in the skin using complementary inflammatory and non-inflammatory mouse models of scleroderma. The proposed studies are expected to establish the role of Nrf2-mediated responses in pathogenesis, and identify novel SO compounds with potent anti-fibrotic activity. Combined with their known antioxidant and immunomodulatory effects, and superior safety profiles, SOs might be highly effective for the therapy of SSc.

描述（由申请人提供）：超过 50% 的侵袭性系统性硬化症 (SSc) 患者在 5 年内死亡或出现器官衰竭，标准化死亡率在过去四十年中保持不变。皮肤和肺纤维化是发病和死亡的主要原因，并且没有批准的治疗方法。纤维化是由受损微环境中肌成纤维细胞激活引起的，由炎症细胞、转化生长因子-ss (TGF-ss) 和活性氧 (ROS) 引发和维持。剖析控制该过程的细胞内信号网络可以导致治疗靶点的发现。我发现 CDDO（天然齐墩果酸的合成衍生物）可以抑制两种不同的硬皮病小鼠模型中的肌成纤维细胞分化并减轻纤维化。因此，CDDO 和具有类似药物特性的相关合成齐墩果烷 (SO) 代表了一种潜在的纤维化治疗方法。此外，我最近发现核因子（红细胞衍生 2）样 2 (Nrf2) 在调节肌成纤维细胞活化和纤维化发展以及介导 CDDO 的抗纤维化作用中具有潜在的关键作用。我的假设是，具有优异安全性的第二代 SO 将在成纤维细胞中表现出 Nrf2 介导的抗纤维化作用，并将减轻 SSc 的关键发病特征（免疫失调、氧化应激和纤维化），并导致小鼠模型中成纤维细胞活化减少、肌成纤维细胞表型逆转并减轻器官纤维化。与博士合作。 Liby 和 Sporn（达特茅斯医学院药理学），我将 i) 使用外植的成纤维细胞、人类皮肤等同物和皮肤类器官，在体外检查两种具有高效诱导 Nrf2 活性的第二代 SO 的抗纤维化作用，并探索作用机制； ii) 使用互补的炎症性和非炎症性硬皮病小鼠模型评估其预防和逆转皮肤纤维化的能力。拟议的研究预计将确定 Nrf2 介导的反应在发病机制中的作用，并鉴定具有有效抗纤维化活性的新型 SO 化合物。结合其已知的抗氧化和免疫调节作用以及卓越的安全性，SO 可能对治疗 SSc 非常有效。