Synthetic Oleananes: Innovative Treatment of Fibrosis

描述(申请人提供)：超过50%的侵袭性系统性硬化症(SSC)患者在5年内死亡或发展为器官衰竭，标准化死亡率在过去40年中保持不变。皮肤和肺纤维化是发病率和死亡率的主要原因，目前还没有得到批准的治疗方法。纤维化是肌成纤维细胞在受损的微环境中活化的结果，由炎症细胞、转化生长因子-ss(TGF-ss)和活性氧(ROS)启动和维持。解剖控制这一过程的细胞内信号网络可以导致发现治疗靶点。我展示了CDDO，一种天然产生的齐墩果酸的合成衍生物，在两种不同的硬皮病小鼠模型中抑制肌成纤维细胞分化和减轻纤维化。因此，CDDO和相关的具有类药物性质的合成齐墩(SOS)代表了一种潜在的治疗纤维化的方法。此外，我最近发现了核因子(红系衍生的2)样2(NRF2)在调控肌成纤维细胞的激活和纤维化的发展以及CDDO的抗纤维化作用中的一个潜在的关键作用。我的假设是，具有良好安全性的第二代SOS将在成纤维细胞中显示Nrf2介导的抗纤维化作用，并将缓解SSC(免疫调节失调、氧化应激和纤维化)的关键病理特征，导致成纤维细胞激活减少，肌成纤维细胞表型逆转，并减轻小鼠器官纤维化。与Liby博士和Sporn博士(达特茅斯医学院药理学)合作，我将：i)利用移植的成纤维细胞、人类皮肤的等效物和皮肤器官，检测两种高效的第二代SoS体外诱导Nrf2活性的抗纤维化效果，并探索其作用机制；ii)使用硬皮病的补充性炎症和非炎症小鼠模型，评估它们预防和逆转皮肤纤维化的能力。这些研究有望确定Nrf2介导的反应在发病机制中的作用，并鉴定具有强大抗纤维化活性的新的SO化合物。结合已知的抗氧化和免疫调节作用以及卓越的安全性，SOS可能是治疗SSc的高度有效的药物。

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.