Molecular Mechanisms of Portal Hypertension

门静脉高压症的分子机制

• 批准号: 7849410
• 负责人: VIJAY H. SHAH
• 金额: $ 1.69万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-05-15 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7849410
• 关键词: ABL1 gene; Accounting; Actin-Binding Protein; Animal Model; Arts; Blood Vessels; Cell membrane; Cells; Cirrhosis; Cyclic GMP-Dependent Protein Kinases; Data; Defect; Development; Discontinuous Capillary; Filopodia; Fingers; GTP-Binding Proteins; Goals; Hepatic Stellate Cell; Human; Imatinib; Immigration; In Vitro; Liver; Liver Cirrhosis; Mediating; Membrane; Methodology; Molecular; Monomeric GTP-Binding Proteins; Morbidity - disease rate; Nitric Oxide; Nitric Oxide Donors; Nitric Oxide Pathway; Pathogenesis; Pathway interactions; Phosphodiesterase Inhibitors; Phosphotransferases; Portal Hypertension; Portal Pressure; Process; Protein Tyrosine Kinase; Proteins; Proto-Oncogene Proteins c-abl; Signal Pathway; Signal Transduction; Structure; Symptoms; Testing; Translations; Tube; Vasodilator Agents; base; c-abl Proto-Oncogenes; cell motility; cytokine; in vivo; innovation; migration; mortality; novel; novel strategies; novel therapeutic intervention; vasoconstriction

DESCRIPTION (provided by applicant): Portal hypertension and its complications account for much of the morbidity and mortality associated with cirrhosis. The long-term goal of our lab is to understand the molecular control mechanisms of portal hypertension. Sinusoidal vasoconstriction is an essential component in the development of portal hypertension and occurs through contraction of hepatic stellate cells (HSC). However, the process by which these contractile HSC organize and wrap around the sinusoidal channel in cirrhosis, is enigmatic. Our studies have focused on migration signals in HSC that contribute to this process of "sinusoidal remodeling". Our exciting preliminary data demonstrates that 1) the small GTPase Rac and the actin-binding protein, VASP, promote HSC migration by generating finger-like filopodia from the plasma membrane, 2) Ableson tyrosine kinase (c- abl) promotes HSC-mediated formation of vascular tubes in vitro, 3) the multifunctional cytokine, nitric oxide (NO) inhibits filopodia formation and HSC-driven vascular tube formation through a protein kinase G (PKG)- dependent pathway, and 4) defects in migration signaling in HSC from animal models of portal hypertension are associated with increased sinusoidal coverage by HSC and an ensuing increase in portal pressure, pointing to an in vivo relevance of the proposed pathways. We have parlayed these novel findings into the central hypothesis that; Rac, acting in tandem with its regulatory partners, VASP and c-abl, maintains a molecular counterbalance with NO that governs the formation of membrane filopodia and HSC-driven vascular tubes. Alterations in this counterbalance influence portal pressure by regulating the level of coverage of the sinusoids by contractile HSC. The Specific Aims of the proposal are to test the three subhypotheses that: 1) Rac dependent filopodia formation in HSC is inhibited by NO through PKG dependent inactivation of the Rac effector protein, VASP, 2) C-abl governs HSC-driven vascular tube formation through pathways regulated by Rac and NO, and which are augmented in portal hypertension, and 3) the counterbalance of Rac and NO in HSC regulates sinusoidal remodeling and portal hypertension in vivo. Thus, this proposal will use state-of-the- art methodologies and world-renown collaborators, to elucidate novel signaling pathways in HSC that contribute to portal hypertension, which in turn will set a trajectory towards new therapeutic approaches towards portal hypertension and its symptoms.

描述（由申请人提供）：门静脉高压症及其并发症是肝硬化相关发病率和死亡率的主要原因。我们实验室的长期目标是了解门脉高压的分子控制机制。正弦血管收缩是门静脉高压发生的重要组成部分，通过肝星状细胞 (HSC) 的收缩而发生。然而，在肝硬化中，这些收缩性 HSC 组织并包裹在肝窦周围的过程仍然是个谜。我们的研究重点是 HSC 中有助于“正弦重塑”过程的迁移信号。我们令人兴奋的初步数据表明，1) 小 GTPase Rac 和肌动蛋白结合蛋白 VASP 通过从质膜生成指状丝状伪足来促进 HSC 迁移，2) Ableson 酪氨酸激酶 (c-abl) 促进 HSC 介导的形成体外血管的形成，3) 多功能细胞因子一氧化氮 (NO) 通过蛋白激酶 G (PKG) 依赖性抑制丝状伪足形成和 HSC 驱动的血管形成途径，4) 门脉高压动物模型中 HSC 迁移信号的缺陷与 HSC 正弦波覆盖范围的增加以及随后门静脉压力的增加有关，这表明所提出的途径具有体内相关性。我们将这些新颖的发现转化为中心假设： Rac 与其调节伙伴 VASP 和 c-abl 协同作用，与 NO 保持分子平衡，控制膜丝状伪足和 HSC 驱动的血管的形成。这种平衡的改变通过调节收缩性 HSC 的正弦波覆盖水平来影响门静脉压力。该提案的具体目标是测试三个子假设：1) NO 通过 PKG 依赖性 Rac 效应蛋白 VASP 失活来抑制 HSC 中的 Rac 依赖性丝状伪足形成，2) C-abl 控制 HSC 驱动的血管形成通过 Rac 和 NO 调节的途径，这些途径在门静脉高压症中增强，3) HSC 中 Rac 和 NO 的平衡调节正弦曲线体内重塑和门脉高压。因此，该提案将使用最先进的方法和世界知名的合作者来阐明 HSC 中导致门静脉高压的新信号通路，这反过来将为门静脉高压及其症状的新治疗方法奠定基础。 。