Dissecting the Acid Ceramidase Pathway in Hepatic Fibrogenesis

剖析肝纤维形成中的酸性神经酰胺酶途径

• 批准号: 10736680
• 负责人: Jennifer Y. Chen
• 金额: $ 52.91万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-15 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10736680
• 关键词: Ablation; Affect; American; Atomic Force Microscopy; Biochemical; Biological Assay; Biological Markers; Cells; Ceramide Signaling Pathway; Ceramides; Cessation of life; Characteristics; Chronic; Clinical; Clinical Treatment; Collagen; Data; Deposition; Development; Diagnosis; Diagnostic tests; Disease; Disease Progression; Enzymes; Extracellular Matrix; Extracellular Matrix Degradation; FDA approved; Fibrosis; Genes; Goals; Hepatic Fibrogenesis; Hepatic Stellate Cell; Human; Hydrolysis; In Vitro; Interstitial Collagenase; Knockout Mice; Knowledge; Life; Liver; Liver Failure; Liver Fibrosis; Matrix Metalloproteinases; Mediating; Mediator; Mission; Modeling; Modification; Molecular; Outcome; Pathway interactions; Patients; Play; Public Health; Publishing; Regulation; Research; Resolution; Role; STK11 gene; Sampling; Severities; Signal Pathway; Signal Transduction; Stress; Techniques; Testing; Therapeutic; United States National Institutes of Health; Work; antifibrotic treatment; attenuation; chronic liver disease; clinical diagnostics; clinically relevant; cohort; conditional knockout; disease heterogeneity; effective therapy; end stage liver disease; fibrogenesis; gain of function; galactosylgalactosylglucosylceramidase; genetic signature; improved; in vivo; loss of function; non-alcoholic fatty liver disease; novel therapeutics; patient biomarkers; patient population; patient subsets; personalized medicine; prevent; response; side effect; specific biomarkers

ABSTRACT Fibrosis is the final common pathway in chronic liver disease that leads to liver failure, and is characterized by an imbalance of extracellular matrix (ECM) deposition and remodeling. There are currently no FDA-approved therapies to target this endpoint of chronic liver disease. Moreover, there is a paucity of biomarkers that reflect disease-specific pathways in patients. Development of new therapeutics and biomarkers for patients with hepatic fibrosis is a critical unmet need. Our long-term goal is to develop antifibrotic therapies for the treatment of hepatic fibrosis and to develop biomarkers to define the patient populations that would benefit most from these therapies. Our prior studies discovered an antifibrotic target, the enzyme acid ceramidase (aCDase). Targeting aCDase ameliorates fibrosis by inhibiting YAP/TAZ, key effectors of the Hippo pathway, and promotes ECM remodeling. We developed a signature score of genes downregulated by ceramide, the Ceramide Responsiveness score (CRS), and demonstrated that the CRS is increased in patients with advanced fibrosis. Despite the fact that targeting aCDase in HSCs ameliorates activation in culture and ablating its expression prevents liver fibrosis in vivo, chronic ceramide accumulation may have untoward side effects. The overall objective of the proposal is to clarify the mechanisms by which ceramide regulates YAP/TAZ, ECM remodeling, and hepatic fibrosis. We also seek to validate the CRS as a pathway-specific biomarker in patients with hepatic fibrosis. The rationale for this project is that understanding the mechanisms of ceramide-mediated attenuation of HSC activation and hepatic fibrosis will offer a strong scientific framework to facilitate the development of antifibrotic therapeutics and biomarkers for patients. To achieve this objective, this proposal has three specific aims. In specific aim 1, we will determine the mechanism by which ceramide regulates Hippo signaling. In specific aim 2, we will characterize how ceramide regulates ECM remodeling. Specific aims 1 and 2 will be achieved by gain of function and loss of function techniques in vitro and testing HSC-specific knockout mice. In specific aim 3, we will analyze the correlation between the CRS, fibrosis stage, and fibrosis progression using deidentified human liver samples, and will identify clinical characteristics that correlate with the CRS. The mechanistic understanding to be gained from the successful completion of the proposed studies promises to reveal new targets for rational disease modification in hepatic fibrosis, a disease with limited treatment options available. Furthermore, by clarifying molecular mechanisms and defining a pathway-specific signature, our work will facilitate a personalized medicine approach for patients with hepatic fibrosis.

抽象的 纤维化是导致肝衰竭的慢性肝病的最终常见途径，其特征是 细胞外基质（ECM）沉积和重塑的不平衡。目前没有FDA批准 针对慢性肝病的终点的疗法。而且，反映的生物标志物很少 患者的疾病特异性途径。为肝患者开发新的治疗剂和生物标志物 纤维化是至关重要的未满足需求。我们的长期目标是开发抗纤维化疗法以治疗肝 纤维化并开发生物标志物来定义将受益于这些疗法的患者种群。 我们先前的研究发现了一个抗纤维化靶标，酶酸神经酶（ACDase）。靶向ACDase 通过抑制YAP/TAZ，河马途径的关键效应子来改善纤维化，并促进ECM重塑。 我们开发了一个由神经酰胺下调的基因的签名评分，即神经酰胺的响应得分 （CRS），并证明晚期纤维化患者的CRS增加。尽管事实 HSC中的靶向ACDase可以改善培养物中的激活，并消除其表达，可防止肝纤维化 体内，慢性神经酰胺的积累可能具有不良的副作用。该提案的总体目标是 阐明神经酰胺调节YAP/TAZ，ECM重塑和肝纤维化的机制。我们也是 寻求在肝纤维化患者中验证CRS为途径特异性生物标志物。理由 项目是了解神经酰胺介导的HSC激活和肝的衰减的机制 纤维化将提供强大的科学框架，以促进抗纤维化治疗剂的发展和 患者的生物标志物。为了实现这一目标，该提案具有三个具体目标。在特定目标1中，我们将 确定神经酰胺调节河马信号传导的机制。在特定目标2中，我们将描述 神经酰胺如何调节ECM重塑。特定的目标1和2将通过功能增长和损失来实现 体外和测试HSC特异性基因敲除小鼠的功能技术。在特定目标3中，我们将分析 CRS，纤维化阶段和纤维化进展之间的相关性使用去识别的人肝样品， 并将确定与CRS相关的临床特征。要获得的机械理解 从成功完成拟议的研究后，有望揭示有关理性疾病的新目标 肝纤维化的修饰，这种疾病有限的治疗选择。此外，通过澄清 分子机制并定义特定途径的签名，我们的工作将促进个性化药物 肝纤维化患者的方法。