The retinoid burst in hepatic stellate cell mediated 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（NAFLD），酒精和丙型肝炎病毒感染，估计有超过1000万人患有肝硬化。这些患者中的许多人患有使人衰弱的后遗症，导致生活质量下降，并给医疗保健系统带来沉重负担。Rockey实验室目前正在阐明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被激活并从称为脂滴的专门细胞器中失去其维生素A储存。维甲酸（RA），维生素A的生物化学活性衍生物，作为类维生素A信号级联的介质，已知具有促纤维化和促肿瘤发生特性的途径。此外，初步数据表明，RA信号传导在TGF β信号传导中重要的分子途径上起重要作用，该途径与星状细胞活化和纤维化密切相关，这支持了以下假设： 脂滴导致细胞内RA的释放，这反过来对细胞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脂滴中维生素A损失的分子基础也是未知的。鉴于此信息，本申请提出以下假设：1）肝损伤导致类维生素A爆发期间从脂滴释放RA，引起HSC的活化，2）从脂滴释放RA导致在活化的HSC中观察到的脂滴耗尽，3）特异性酶，视黄醛脱氢酶1（RALDH 1）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激活的触发器，并且RA释放的阻断将维持HSC处于静止状态。本提案的目的是表征活化的HSC中的类维生素A爆发，以确定类维生素A爆发的调节和下游效应，并了解RALDH 1在体内肝损伤过程中调节RA信号传导的作用。这项研究将描绘在受损的HC类维生素A爆发，并确定类维生素A代谢与TGF β信号转导的事件。所有证据表明，这种级联反应是有效的，并且可以用于开发抗纤维化药物以消除高危个体中的肝纤维化和肝硬化。该NRSA提案的培训部分旨在建立在候选人的研究技能基础上，并促进她作为一名医生-科学家的培训，进行高影响力的基础研究，有可能改善需要医疗独创性的患者。该培训计划是申请人在肝纤维化领域建立独立研究生涯的基础。

 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.