Molecular Mechanisms of Portal Hypertension

门静脉高压症的分子机制

• 批准号: 7899760
• 负责人: VIJAY H. SHAH
• 金额: $ 31.79万
• 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 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7899760
• 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）：门户高血压及其并发症造成了与肝硬化相关的大部分发病率和死亡率。我们实验室的长期目标是了解门户高血压的分子控制机制。正弦血管收缩是门户高血压发展的重要组成部分，并通过肝星状细胞（HSC）收缩而发生。但是，这些收缩HSC在肝硬化中组织和包裹正弦通道的过程是神秘的。我们的研究集中在HSC中的迁移信号上，这有助于这种“正弦重塑”过程。 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通过蛋白激酶G（PKG） - 依赖性途径和4）HSC迁移信号的缺陷从门户高血压的动物模型中迁移信号传导缺陷，与HSC的正弦覆盖增加有关，并导致门户上的增加，指向Invivo相关的途径，HSC的迁移信号传导与肾上腺体性增加有关。我们将这些新颖的发现纳入了一个中心假设。 RAC与其调节伙伴VASP和C-ABL一起起作用，维持了分子平衡，而没有控制膜丝状丝状膜和HSC驱动的血管管的形成。这种反平衡的变化通过调节收缩性HSC的正弦曲线覆盖水平来影响门户压力。 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调节体内正弦重塑和门户高血压。因此，该提案将使用最先进的方法和世界享有的合作者来阐明HSC中有助于门户高血压的新型信号通路，这反过来又将为通往门户高血压及其症状的新治疗方法构成轨迹。