The retinoid burst in hepatic stellate cell mediated liver fibrosis

肝星状细胞介导的肝纤维化中的类维生素A爆发

• 批准号: 8909992
• 负责人: Loretta L. Jophlin
• 金额: $ 5.6万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-01-01 至 2018-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8909992
• 关键词: Address; Adipocytes; Alcohols; American; Area; Basic Science; Biology; Carbon Tetrachloride; Cells; Cellular biology; Cessation of life; Chronic; Cicatrix; Cirrhosis; Collagen; Data; Development; Disease; Enzymes; Event; Extracellular Matrix Proteins; Fibronectins; Fibrosis; Fostering; Foundations; Future; Gene Expression Regulation; Generations; Goals; Health Care Costs; Healthcare Systems; Hepatic Fibrogenesis; Hepatic Stellate Cell; Hepatitis C; Hepatology; Human; In Vitro; Individual; Injury; Investigation; Knockout Mice; Knowledge; Laboratories; Ligands; Ligation; Link; Lipids; Liver; Liver Cirrhosis; Liver Fibrosis; Liver diseases; Mediating; Mediator of activation protein; Medical; Metabolism; MicroRNAs; Molecular; Morbidity - disease rate; Myofibroblast; National Research Service Awards; Organelles; Pathway interactions; Patients; Phosphorylation; Physicians; Play; Process; Production; Property; Quality of life; Regulation; Research; Research Personnel; Retinoids; Risk; Rodent Model; Role; Scientist; Signal Pathway; Signal Transduction; Site; Smooth Muscle Actin Staining Method; Time; Training; Transforming Growth Factor beta; Tretinoin; United States; Vitamin A; Wound Healing; base; bile duct; career; career development; clinically significant; design; experience; fibrogenesis; in vivo; injured; knowledge base; liver injury; mortality; mouse model; non-alcoholic fatty liver; novel strategies; premature; prevent; public health relevance; receptor; response; retinaldehyde dehydrogenase; skills; stellate cell; therapeutic target; tumorigenic

 DESCRIPTION (provided by applicant): Cirrhosis represents the liver's response to chronic injury. In the US, the most common causes of cirrhosis include nonalcoholic fatty liver disease (NAFLD), alcohol, and hepatitis C virus infection and it is estimated that over 10 million people have cirrhosis. Many of these patients suffer from debilitating sequela, resulting in decreased quality of life and placing a heavy burden on the healthcare system. The Rockey Laboratory is currently elucidating the mechanisms controlling hepatic fibrosis with the ultimate goal of developing anti- fibrotic therapies to abrogate or reverse cirrhosis in at-risk individuals. Extensive investigation points to the activated hepatic stellate cell (HSC) as the primary cell typ responsible for mediating the fibrogenic response. This cell is also the predominant storage site for vitamin A in the body. However, during liver injury, and the development of fibrosis and cirrhosis, HSCs become activated and lose their vitamin A stores from specialized organelles known as lipid droplets. Retinoic acid (RA), the biochemically active derivative of vitamin A, serves as a mediator of the retinoid signaling cascade, a pathway known to have profibrotic and pro-tumorigenic properties. Further, preliminary data indicate that RA signaling plays an important role on molecular pathways important in TGFß signaling, a pathway critically linked to stellate cell activation and fibrogenesis supporting the postulate that depletion of vitamin A from lipid droplets leads to release of RA within the cell, which in turn has critical molecular effectsin the cell. The vitamin A depletion event is termed herein the "retinoid burst". The molecular basis for the loss of vitamin A from HSC lipid droplets is also unknown. Given this information, this application proposes the following hypothesis: 1) Liver injury results in RA release from lipid droplets during the retinoid burst causing the activation of HSCs, 2) RA release from lipid droplets leads to lipid droplet depletion seen in activated HSCs, 3) A specific enzyme, retinaldehyde dehydrogenase 1 (RALDH1) is responsible for RA release during the retinoid burst and 4) RA release during the retinoid burst is the trigger for HSC activation and blockade of RA release will maintain HSCs in a quiescent state. The aims of this proposal are to characterize the retinoid burst in activated HSCs, to determine the regulation of and downstream effects of the retinoid burst, and to understand the role of RALDH1 in regulating RA signaling during in vivo liver injury. This research will delineate the retinoid burst in injured HCs and determine the events connecting retinoid metabolism with TGFß signaling. All evidence suggests this cascade is potent and a target that can be harnessed for the development of anti-fibrotic agents to abrogate hepatic fibrosis and cirrhosis in at-risk individuals. The training portion of this NRSA proposal is designed to build upon the candidate's research skills and foster her training as a physician-scientist performing high-impact basic research with potential to better patients in need of medical ingenuity. This training plan is the foundation on which the applicant will establish an independent research career in the field of liver fibrosis.

 描述（由适用提供）：肝硬化代表肝脏对慢性损伤的反应。在美国，肝硬化的最常见原因包括非酒精性脂肪肝病（NAFLD），酒精和丙型肝炎病毒感染，据估计，超过1000万人患有肝硬化。这些患者中的许多患者患有令人衰弱的后遗症，导致生活质量降低，并在医疗系统上施加了沉重的烧伤。 Rockey实验室目前正在阐明控制肝纤维化的机制，其最终目的是开发抗纤维化疗法以消除或反向肝硬化。广泛的投资指向激活的肝星状细胞（HSC），是负责介导纤维源反应的主要细胞。该细胞也是体内维生素A的主要存储位点。然而，在肝损伤以及纤维化和肝硬化的发育过程中，HSC被激活并损失其维生素A储存量的专用细胞器，称为脂质液滴。维生素A的生物化活性衍生物的视黄酸（RA）充当性类视黄素信号级联的介体，这是一种已知具有纤维化和亲富特性的途径。此外，初步数据表明RA信号在TGFß信号中很重要的分子途径中起着重要作用，这是一种与星状细胞激活和纤维发生密切相关的途径，该途径支持假设从 脂质液滴导致RA在细胞内释放，进而在细胞中具有关键的分子作用。维生素的部署事件在本文中称为“类维生素爆发”。从HSC脂质液滴中丧失维生素A的分子基础也未知。 Given this information, this application proposals the following hypothesis: 1) Liver injury results in RA release from lipid droplets during the retinoid burst causing the activation of HSCs, 2) RA release from lipid droplets leads to lipid droplet definition seen in activated HSCs, 3) A specific enzyme, retinaldehyde dehydrogenase 1 (RALDH1) is responsible for RA release during the retinoid burst and 4) RA类维生素类动物爆发期间的释放是HSC激活的触发因素，RA释放的阻滞将保持HSC处于静止状态。该提案的目的是表征活化的HSC中的类维生素类动物爆发，以确定类维生素类动物爆发的调节和下游效应，并了解Raldh1在控制体内肝损伤过程中控制RA信号传导中的作用。这项研究将描绘受伤的HCS中的类维生素类动物爆发，并确定将视视视网膜代谢与TGFß信号传导联系起来的事件。所有证据表明，这种级联反应是潜在的，并且可以利用抗纤维化药物来消除高危个体中肝纤维化和肝硬化的目标。该NRSA建议的培训部分旨在以候选人的研究技能为基础，并培养她作为身体科学家进行高影响力基础研究的培训，并有可能更好地需要医疗性的患者。该培训计划是申请人将在肝纤维化领域建立独立研究职业的基础。