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 纤维化是慢性肝病导致肝衰竭的最终共同途径，其特点是 细胞外基质（ECM）沉积和重塑的不平衡。目前还没有 FDA 批准的 针对慢性肝病这一终点的治疗方法。此外，很少有生物标志物能够反映 患者的疾病特异性途径。肝病患者新疗法和生物标志物的开发 纤维化是一个未得到满足的关键需求。我们的长期目标是开发抗纤维化疗法来治疗肝病 纤维化并开发生物标志物来定义将从这些疗法中受益最多的患者群体。 我们之前的研究发现了一种抗纤维化靶标，即酸性神经酰胺酶（aCDase）。靶向 aCDase 通过抑制 Hippo 通路的关键效应子 YAP/TAZ 改善纤维化，并促进 ECM 重塑。 我们开发了神经酰胺下调基因的特征评分，即神经酰胺反应评分 (CRS)，并证明晚期纤维化患者的 CRS 增加。尽管事实上 靶向 HSC 中的 aCDase 可改善培养物中的激活，消除其表达可预防肝纤维化 在体内，慢性神经酰胺积累可能会产生不良副作用。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 寻求验证 CRS 作为肝纤维化患者的通路特异性生物标志物。这样做的理由 该项目的目的是了解神经酰胺介导的 HSC 活化和肝功能减弱的机制 纤维化将为促进抗纤维化疗法的开发提供强大的科学框架 患者的生物标志物。为了实现这一目标，该提案有三个具体目标。在具体目标1中，我们将 确定神经酰胺调节 Hippo 信号传导的机制。在具体目标 2 中，我们将描述 神经酰胺如何调节 ECM 重塑。具体目标 1 和 2 将通过功能的获得和功能的丧失来实现 体外功能技术和测试 HSC 特异性敲除小鼠。在具体目标 3 中，我们将分析 使用未识别的人类肝脏样本研究 CRS、纤维化阶段和纤维化进展之间的相关性， 并将识别与 CRS 相关的临床特征。需要获得的机械理解 拟议研究的成功完成有望揭示合理疾病的新目标 肝纤维化是一种治疗选择有限的疾病。此外，通过澄清 分子机制并定义特定途径的特征，我们的工作将促进个性化医疗 肝纤维化患者的治疗方法。