Rac1 Promotes Hepatic Stellate Accumulation/Activation in Liver Injury

Rac1 促进肝损伤中肝星状细胞的积累/激活

• 批准号: 8631145
• 负责人: Steve S Choi
• 金额: $ 0.05万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-22 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8631145
• 关键词: Address; Adenovirus Vector; Agonist; Apoptosis; Benign; Biological Models; Cell Count; Cell Proliferation; Cells; Chronic; Cicatrix; Cirrhosis; Cytoskeletal Proteins; Dominant-Negative Mutation; Epithelial; Erinaceidae; Etiology; Event; Fatty acid glycerol esters; Gene Expression; Genetic; Goals; Growth; Health; Hepatic; Hepatic Stellate Cell; Hepatocyte; In Vitro; Injury; Liver; Liver Dysfunction; Mediating; Mediator of activation protein; Mesenchymal; Morbidity - disease rate; Pathogenesis; Pathway interactions; Phenotype; Population; Principal Investigator; Process; Proteins; Publications; Signal Transduction; Stem cells; Toxin; Transgenic Animals; United States; epithelial to mesenchymal transition; in vivo Model; liver injury; mortality; novel; regenerative; response; smoothened signaling pathway; stellate cell

DESCRIPTION (provided by applicant): Hepatic accumlation [sic] of myofibroblastic hepatic stellate cells (MF-HSC) is pivotal in the pathogenesis of cirrhosis. Two events are necessary for MF-HSC to accumulate in damaged livers: 1) transition of resident, quiescent HSC (Q-HSC) to MF-HSC, and 2) further expansion of MF-HSC numbers via increased proliferation and/or reduced apoptosis. Our group has identified two novel mediators of MF-HSC accumulation: Rac1 and Hedgehog (Hh). Recently, we have accumulated evidence that the first event (transition to MF-HSC) involves epithelial-to-mesenchymal (EMT) and shown that Hh signaling promotes EMT in another type of resident liver cell (ie, ductular-type progenitors cells (DPC)). Our earlier publications demonstrate that both Rac1 and Hh promote proliferation of MF-HSC while inhibiting their apoptosis. The general goal of this project is to determine if Rac1 and Hh interact to regulate the accumulation of MF-HSC after liver damage. This project evaluates the HYPOTHESIS that Rac1 promotes the activation of the Hh pathway, thereby stimulating signals that promote epithelial-to-mesenchymal transition in Q-HSC, and that enhance the viability of MF-HSC. Two Specific Aims will be addressed: Aim 1 will determine if Rac1 inhibits Hedgehog-interacting protein (Hip) to promote Hh signaling-mediatd [sic] EMT in HSC; Aim 2 will determine the impact of altering Rac1 activity on Hh pathway activation and liver fibrotic response to toxin-induced liver injury. In both in vitro and in vivo model systems, Rac1 signaling will be manipulated via genetic approaches (eg, adenoviral vector-mediated delivery of constitutively active or dominant negative Rac1) and pharmacologic agents (eg, pathway agonists and antagonists). We hope to delineate a signaling cascade by which the cytoskeletal protein Rac1 interacts with a morphogenic signaling pathway (Hh) to reprogram gene expression in Q-HSC, promoting myofibroblastic transition, and enhancing MF-HSC proliferation and survival.

描述（由申请人提供）： 肌纤维细胞肝星状细胞（MF-HSC）的肝积聚[SIC]在肝硬化的发病机理中是关键的。 MF-HSC在受损的肝脏中积累的两个事件是必要的：1）居民静止的HSC（Q-HSC）向MF-HSC过渡，以及2）通过增加的增殖和/或减少凋亡，进一步扩大MF-HSC数字。 。我们的小组已经确定了MF-HSC积累的两个新型介质：Rac1和Hedgehog（HH）。最近，我们积累了证据表明，第一个事件（向MF-HSC的过渡）涉及上皮到间质（EMT），并表明HH信号在另一种类型的居民肝细胞中促进EMT（即，ductular-type型祖细胞（DPC）（DPC） ）。我们较早的出版物表明，Rac1和HH均促进MF-HSC的扩散，同时抑制其凋亡。该项目的一般目标是确定Rac1和HH是否相互作用以调节肝损伤后MF-HSC的积累。该项目评估了Rac1促进HH途径的激活的假设，从而刺激了促进Q-HSC中上皮到间质转变的信号，从而增强了MF-HSC的生存能力。将解决两个具体目标：AIM 1将确定RAC1是否抑制刺猬相互作用蛋白（HIP）以促进HSC中的HH信号 - 媒体[SIC] EMT； AIM 2将确定改变RAC1活性对HH途径激活的影响和对毒素诱导的肝损伤的肝纤维化反应。在体外和体内模型系统中，RAC1信号将通过遗传方法（例如，腺病毒载体介导的组成型活性或显性负RAC1）和药理学剂（例如，途径激动剂和拮抗剂）来操纵。我们希望描绘一个信号级联反应，通过该级联反应，细胞骨架蛋白Rac1与形态学信号通路（HH）相互作用，以在Q-HSC中重编程基因表达，促进肌纤维细胞过渡并增强MF-HSC增殖和存活。

项目成果

Pancreatic secretory trypsin inhibitor I reduces the severity of chronic pancreatitis in mice overexpressing interleukin-1β in the pancreas.

胰腺分泌性胰蛋白酶抑制剂 I 可降低胰腺中过度表达白细胞介素 1β 的小鼠慢性胰腺炎的严重程度。

• DOI: 10.1152/ajpgi.00287.2011
• 发表时间: 2012
• 期刊: American journal of physiology. Gastrointestinal and liver physiology
• 作者: Romac,JoelleM-J;Shahid,RafiqA;Choi,SteveS;Karaca,GamzeF;Westphalen,ChristophB;Wang,TimothyC;Liddle,RodgerA
• 通讯作者: Liddle,RodgerA

Osteopontin is up-regulated in chronic hepatitis C and is associated with cellular permissiveness for hepatitis C virus replication.

• DOI: 10.1042/cs20130473
• 发表时间: 2014-06
• 期刊: Clinical science (London, England : 1979)
• 作者: Choi SS;Claridge LC;Jhaveri R;Swiderska-Syn M;Clark P;Suzuki A;Pereira TA;Mi Z;Kuo PC;Guy CD;Pereira FE;Diehl AM;Patel K;Syn WK
• 通讯作者: Syn WK