Synthetic Oleananes: Innovative Treatment of Fibrosis

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年内死亡或发生器官衰竭，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，并且没有批准的治疗方法。纤维化由损伤微环境中的肌成纤维细胞活化引起，由炎性细胞、转化生长因子-β（TGF-β）和活性氧（ROS）引发和维持。剖析控制这一过程的细胞内信号网络可以发现治疗靶点。我在两种不同的硬皮病小鼠模型中证明了CDDO（一种天然存在的油酸的合成衍生物）抑制肌成纤维细胞分化并减弱纤维化。因此，CDDO和具有药物样性质的相关合成齐墩果烷（SO）代表了纤维化的潜在治疗方法。此外，我最近确定了核因子（红细胞衍生2）样2（Nrf 2）在调节肌成纤维细胞活化和纤维化发展以及介导CDDO的抗纤维化作用中的潜在关键作用。我的假设是，具有优异安全性特征的第二代SO将在成纤维细胞中表现出Nrf 2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和器官纤维化减轻。与Liby和Sporn博士合作（药理学，达特茅斯医学院），我将i）使用体外培养的成纤维细胞、人皮肤等同物和皮肤类器官来检查具有高效力以诱导Nrf 2活性的两种第二代SO的抗纤维化作用，并探索作用机制; ii）使用硬皮病的互补炎性和非炎性小鼠模型评估它们预防以及逆转皮肤纤维化的能力。预计拟议的研究将确定Nrf 2介导的反应在发病机制中的作用，并鉴定具有强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，以及上级安全性特征，SO可能对SSc的治疗非常有效。

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.