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Development of small molecules targeting Nrf2 pathway for treatment of Colitis

开发针对 Nrf2 通路的小分子治疗结肠炎

基本信息

批准号：
8520089
负责人：
Graham P Allaway
金额：
$ 15万
依托单位：
CUREVEDA, LLC
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-06-01 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8520089
关键词：
Affect Anti-Inflammatory Agents Anti-inflammatory Antioxidants Apoptotic Attenuated Chronic Clinical Clinical Drug Development Clinical Trials Colitis Collaborations Colon Complication Crohn&apos s disease Data Analyses Development Dextran Sulfate Disease Doctor of Philosophy Dose Drug Kinetics Drug Metabolic Detoxication Etiology Excretory function Frequencies Functional disorder Future Goals Immune response Incidence Individual Inflammation Inflammatory Inflammatory Bowel Diseases Injury Intervention Intestines Knockout Mice Longitudinal Studies Measures Mediator of activation protein Metabolism Mucous Membrane Mus National Cancer Institute Neutrophil Infiltration Oral Oral Administration Outcome Oxidative Stress Pathogenesis Pathway interactions Patients Pharmaceutical Preparations Pharmacodynamics Pharmacology Phase Positioning Attribute Pre-Clinical Model Predisposition Prevention Principal Investigator Production Property Reaction Reactive Oxygen Species Research Research Personnel Role Scientist Senior Scientist Serum Signal Pathway Signal Transduction Small Business Innovation Research Grant Sodium Dextran Sulfate Submucosa TNF gene Therapeutic Time Tissues Toxic effect Treatment Efficacy Ulcerative Colitis Universities Up-Regulation absorption cytokine design drug candidate drug discovery effective intervention effective therapy efficacy testing innovation mouse model multidisciplinary novel novel therapeutics oxidative damage phase 1 study pre-clinical preclinical study professor programs public health relevance repaired small molecule statistics transcription factor treatment strategy

项目摘要

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.

描述（由申请人提供）：溃疡性结肠炎（UC）是结肠粘膜和粘膜下层的慢性炎症性疾病。尽管 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量的活性氧 (ROS)，这可能导致氧化损伤，从而导致 UC 患者产生氧化应激。 Cureveda 的创始人和其他人使用基因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传导是治疗以下疾病的潜在策略：氧化应激相关的炎症性疾病。转录因子 Nrf2 已成为调节抗氧化防御和先天免疫反应的核心角色。此外，我们的初步证据表明，增强 Nrf2 可以抑制 Th-17 驱动的炎症。 Cureveda 的创始人发现了一种有效的 Nrf2 信号传导小分子激活剂 VEDA-1209，它具有治疗 UC 的潜力。我们假设，VEDA-1209 通过降低氧化反应速率和增加抗氧化反应速率，减少炎症相关损伤。拟议的I期项目旨在评估VEDA-1209治疗溃疡和药效学研究，并通过评估小鼠模型中氧化应激、炎症和组织损伤的标志物来确定其治疗效果。积极的结果将支持 VEDA-1209 在 II 期 SBIR 中的进一步临床前开发。