Fumarates for Alcoholic Liver Disease

富马酸盐治疗酒精性肝病

基本信息

批准号：
10452220
负责人：
Xiaosong Joy Jiang
金额：
$ 19.09万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-10 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10452220
关键词：
Aconitate Hydratase Acute Address Alcoholic Liver Diseases Anti-Inflammatory Agents Antiinflammatory Effect Antioxidants Biochemistry Biogenesis Biological Assay Cessation of life Chronic Complex Data Development Disease model Dose Drug Kinetics FDA approved Fumarates Functional disorder Future Genus Hippocampus Goals Head Hepatocyte In Vitro Inflammatory Inflammatory Response Lead Liver Mediating Mitochondria Modality Modeling Morbidity - disease rate Morphology Motivation Multiple Sclerosis Mus Names National Institute on Alcohol Abuse and Alcoholism Neurodegenerative Disorders Niacinamide Pathogenicity Pathway interactions Pharmaceutical Preparations Preventive Process Prodrugs Property Psoriasis Reaction Reporting Research Role SIRT1 gene Signal Transduction Structure Testing Therapeutic Transplantation Treatment Efficacy Western Blotting analog design effective therapy efficacy evaluation in vivo knock-down liver transplantation macrophage mouse model nonalcoholic steatohepatitis novel novel therapeutic intervention novel therapeutics therapeutic development translational study

项目摘要

Abstract Alcoholic liver disease (ALD) remains the leading lethal liver condition, and the primary reason for transplantation. There is still no effective therapy. Dimethyl fumarate (DMF), a monomethyl fumarate (MMF) prodrug, is an FDA proved therapy for neural degenerative diseases and has We have developed a novel analogue molecule nicotinamide fumarate (NMF) that carries optimized pharmacokinetic characters. Our preliminary data show that NMF significantly ameliorates alcoholic liver injury in mice, and is superior to DMF. been recently reported to rescue alcoholic liver injury in mice. We propose that NMF elicits its protection via three pathways: Nrf2-driven anti-oxidative reaction, Hca2-mediated anti-inflammatory response, and mitochondrial induction. In this study, we will evaluate the preventive and therapeutic efficacy of NMF comparing with RTA408 a drug solely inducing Nrf2, using mouse models of ALD. We will also identify the mechanistic signaling by focusing on Nrf2, Hca2 and mitochondrial functions. The study may lead to the development of new therapeutic modalities and translational studies in the future.

抽象的酒精性肝病（ALD）仍然是主要的致命性肝脏疾病，也是主要原因用于移植。目前还没有有效的治疗方法。富马酸二甲酯 (DMF)，一种单甲基富马酸盐 (MMF) 前药，是 FDA 证明的神经退行性疾病疗法，具有我们开发了一本小说具有优化药代动力学的类似分子富马酸烟酰胺 (NMF) 人物。我们的初步数据表明，NMF 可显着改善酒精性肝损伤小鼠，优于 DMF。最近有报道称它可以挽救小鼠的酒精性肝损伤。我们建议 NMF 通过三种途径引起保护： Nrf2 驱动的抗氧化反应、Hca2 介导的抗炎反应，以及线粒体诱导。在这项研究中，我们将评估以下药物的预防和治疗功效：使用 ALD 小鼠模型，将 NMF 与仅诱导 Nrf2 的 RTA408 进行比较。我们将还通过关注 Nrf2、Hca2 和线粒体功能来确定机制信号传导。该研究可能会导致新的治疗方式和转化研究的发展将来。