Development of small molecules targeting Nrf2 pathway for treatment of Colitis

描述（由申请人提供）：溃疡性结肠炎（UC）是一种结肠粘膜和粘膜下层的慢性炎症性疾病。虽然UC的发病机制是多因素和特发性的，但越来越多的证据表明，促炎介质产生过多的活性氧（ROS），可导致UC患者氧化应激的氧化损伤。Cureveda的创始人和其他人使用敲除小鼠模型进行的概念验证临床前研究表明，选择性激活转录因子信号是治疗糖尿病的一种潜在策略

DESCRIPTION (provided by applicant): Ulcerative colitis (UC) is a chronic inflammatory disorder of the mucosa and submucosa of the colon. Although the pathogenesis of UC is multifactorial and idiopathic, a growing body of evidence suggests that proinflammatory mediators produce excess reactive oxygen species (ROS) which can cause oxidative damage resulting in oxidative stress in UC patients. Proof-of-concept preclinical studies using knockout mouse models conducted by Cureveda's founders and others have demonstrated that the selective activation of transcription factor signaling is a potential strategy for the treatment of oxidative-stress-related inflammatory diseases. The transcription factor Nrf2 has emerged as a central player in regulating antioxidant defenses and innate immune response. In addition, our preliminary evidence suggests that augmenting Nrf2 inhibits Th-17 driven inflammation. Cureveda's founders have identified a potent small molecule activator of Nrf2 signaling, VEDA-1209, which has potential as a therapeutic for UC. We hypothesize that, by reducing the rates of oxidative reactions and increasing the rates of antioxidative reactions, VEDA-1209 reduces inflammation-related injury. The proposed Phase I project aims to evaluate VEDA-1209 for the treatment of ulcerative and pharmacodynamic studies and determining its therapeutic efficacy by evaluating markers of oxidative stress, inflammation and tissue injury in the mouse model. Positive outcomes will support further preclinical development of VEDA-1209 in phase II SBIR.