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: 9033667
• 负责人: Loretta L. Jophlin
• 金额: $ 3.44万
• 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 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9033667
• 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 Transduction; Site; Smooth Muscle Actin Staining Method; TGF Beta Signaling Pathway; 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（由申请人提供）：肝硬化代表肝脏对慢性损伤的反应。在美国，肝硬化最常见的原因包括非酒精性脂肪肝病（NAFLD）、酒精和丙型肝炎病毒感染，估计超过 1000 万人。许多患者患有肝硬化，导致生活质量下降，给医疗保健系统带来沉重负担。控制肝纤维化的机制，最终目标是开发抗纤维化疗法，以消除或逆转高危个体的肝硬化。广泛的研究表明，活化的肝星状细胞（HSC）是负责介导纤维化反应的主要细胞类型。该细胞也是体内维生素 A 的主要储存场所。然而，在肝损伤以及纤维化和肝硬化的发展过程中，HSC 会被激活并失去维生素 A。视黄酸 (RA) 是维生素 A 的生化活性衍生物，是一种已知具有促纤维化和促肿瘤发生特性的途径。 RA 信号传导在 TGFβ 信号传导中发挥着重要作用，该信号传导与星状细胞活化和纤维形成密切相关，支持维生素 A 消耗的假设 脂滴导致细胞内RA的释放，这反过来在细胞中具有关键的分子效应。维生素A消耗事件在本文中被称为“类维生素A爆发”。HSC脂滴损失维生素A的分子基础。鉴于此信息，本申请提出以下假设：1) 肝损伤导致在类视黄醇爆发期间从脂滴中释放 RA，从而导致 HSC 的激活，2) 从脂滴中释放 RA 导致脂质。激活的 HSC 中出现液滴耗尽，3) 一种特定的酶，视黄醛脱氢酶 1 (RALDH1) 负责类维生素A爆发期间的 RA 释放，4) 类维生素A爆发期间的 RA 释放是 HSC 激活的触发因素，并且阻断 RA 释放将维持该提案的目的是表征激活的 HSC 中的类维生素A爆发，以确定其调节和下游影响。类视黄醇爆发，并了解 RALDH1 在体内肝损伤期间调节 RA 信号传导中的作用。这项研究将描述受损 HC 中的类视黄醇爆发，并确定类视黄醇代谢与 TGFβ 信号传导之间的联系。该 NRSA 提案的培训部分旨在建立可用于开发抗纤维化药物以消除高危个体肝纤维化和肝硬化的目标。该培训计划是申请人在该领域建立独立研究生涯的基础。肝纤维化。