The retinoid burst in hepatic stellate cell mediated liver fibrosis

 描述(申请人提供)：肝硬变代表肝脏对慢性损伤的反应。在美国，导致肝硬变的最常见原因包括非酒精性脂肪性肝病(NAFLD)、酒精和丙型肝炎病毒感染，据估计，超过1000万人患有肝硬变。其中许多患者患有衰弱的后遗症，导致生活质量下降，并给医疗保健系统带来沉重负担。罗基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变。广泛的研究表明，活化的肝星状细胞(HSC)是介导纤维化反应的主要细胞类型。这个细胞也是体内维生素A的主要储存场所。然而，在肝损伤、纤维化和肝硬化的发展过程中，HSC被激活，失去了被称为脂滴的特殊细胞器中的维生素A储存。维甲酸(RA)是维生素A的生物化学活性衍生物，是维甲酸信号通路的中介物，该通路具有促纤维化和促肿瘤的特性。此外，初步数据表明，RA信号在转化生长因子B信号通路中的重要分子通路中发挥重要作用，这一通路与星状细胞激活和纤维化形成密切相关，支持维生素A从 脂滴导致维甲酸在细胞内释放，进而在细胞内产生关键的分子效应。维生素A的耗竭事件在这里被称为“类维甲酸爆发”。从HSC脂滴中损失维生素A的分子基础也是未知的。鉴于这些信息，本应用提出以下假设：1)肝脏损伤导致在视黄醇爆裂期间从脂滴中释放RA导致HSC激活，2)从脂滴中释放RA导致激活的HSC中的脂滴耗尽，3)一种特定的酶，视黄醛脱氢酶1(RALDH1)负责在视黄醇爆裂期间释放RA，4)在视黄醇爆裂期间RA释放是HSC激活的触发因素，阻止RA释放将使HSC保持静止状态。本研究的目的是确定活化的HSC中的维甲酸爆发的特征，确定维甲酸爆发的调节和下游效应，并了解RALDH1在体内肝损伤过程中调节RA信号的作用。这项研究将描绘受损的HCS中的维甲酸的爆发，并确定维甲酸代谢与转化生长因子？信号有关的事件。所有证据表明，这种级联反应是有效的，可以作为开发抗纤维化药物的靶点，以消除高危个体的肝纤维化和肝硬变。该NRSA提案的培训部分旨在以候选人的研究技能为基础，并培养她作为一名内科科学家的培训，执行具有高影响力的基础研究，有可能改善需要医疗独创性的患者。这项培训计划是申请者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.