Synthetic Oleananes: Innovative Treatment of Fibrosis

合成齐墩果烷：纤维化的创新治疗方法

基本信息

批准号：
8917095
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
项目类别：
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/8917095
关键词：
Acids 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

项目摘要

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（由适用提供）：超过50％的系统性硬化症（SSC）在5年内死亡或发展器官衰竭的患者，并且在过去的四十年中一直保持不变。皮肤和肺纤维化是发病率和死亡率的主要原因，没有批准的治疗方法。纤维化是由受伤的微环境中的肌纤维细胞激活引起的，该环境由炎症细胞引发和维持，转化生长因子-β（TGF-ß）和活性氧（ROS）。解剖控制过程的细胞内信号网络可以导致发现治疗靶标。我表明，在两种不同的硬皮病小鼠模型中，CDDO是天然存在的灰醇酸的合成衍生物，抑制了肌纤维细胞分化和减弱纤维化。因此，具有类似药物的特性的CDDO及相关的合成蛋白质（SOS）代表了一种潜在的纤维化治疗方法。此外，我最近确定了核因子（红细胞衍生的2）类似2（NRF2）在调节纤维细胞激活和纤维化发展以及介导CDDO的抗纤维化作用中的潜在关键作用。 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 pathogenic 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.与Drs合作。 Liby and Sporn（Dartmouth医学院药理学），我将i）检查两种第二代SOS具有高效力的抗纤维化作用，可使用外植入的成纤维细胞，人类皮肤等效物和皮肤器官在体外诱导NRF2活性，并探索作用机制； ii）评估其使用硬皮病的互补炎症和非炎性小鼠模型来评估皮肤中纤维化的能力。预计拟议的研究将确定NRF2介导的反应在发病机理中的作用，并鉴定具有潜在抗纤维化活性的新型化合物。结合其已知的抗氧化剂和免疫调节作用以及出色的安全性，SOS可能对SSC的治疗非常有效。